Dibenzocycloheptatone derivatives and pharmaceutical agents containing said compounds

ABSTRACT

The present invention relates to compounds of the formula I 
     
       
         
         
             
             
         
       
     
     wherein R1, R2, R3, R4, X and Y have the meanings given in the description. The compounds have an action which is immunomodulating and inhibits or regulates the release of IL-1β and/or TNF-α. They can therefore be used for treatment of diseases connected with a disturbance in the immune system.

The present invention relates to compounds of the formula I

wherein X, Y and R1 to R4 have the meanings given below, andpharmaceutical compositions which contain the compounds of the formulaI. The compounds are interleukin-1β (IL-1β) and tumor necrosis factor α(TNF-α) inhibitors which can be used for treatment of inflammatorydiseases.

IL-1β and TNF-α protect the body against infectious agents, tumors ortissue damage. In the case of autoimmune diseases, however, an increasedproduction of IL-1β and TNF-α occurs, which can result, for example, inthe degeneration of bone and cartilage. Drugs which regulate the releaseof IL-β and TNF-α can therefore be used for treatment of inflammatorydiseases.

One group of compounds which inhibit the release of IL-1β and TNF-α areknown from WO 98/32730. They correspond to the general formula

and can be used for treatment and prophylaxis of asthma, allergies,rheumatoid arthritis, spondyloarthritis, gout, atherosclerosis, chronicinflammatory bowel disease, proliferative and inflammatory skindiseases, such as psoriasis and atopic dermatitis.

Further compounds of this group are described in WO 01/05744, WO01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/42189, WO02/45752, WO 02/076447 and WO 03/018535 and in J. Med. Chem. 2003, 46,5651-5662 and Bioorganic & Medicinal Chemistry Letters 14 (2004)3601-3605.

WO 2006/120010 describes dibenzocycloheptanone derivatives of theformula I

wherein one of the ring atoms X and Y represents CH₂ and the otherrepresents O, S, SO, SO₂ or NR5; or —X—Y— represents —CH₂—CH₂— or—CH═CH—; R1 represents H or C₁-C₆-alkyl; and R2 represents H, halogen orC₁-C₄-alkyl-C≡C—, which is optionally substituted by an amino group. R3represents halogen or an optionally substituted amino radical. Thecompounds are interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α)inhibitors which can be used for treatment of inflammatory diseases.

However, the action of the compounds is not satisfactory.

The present invention is therefore based on the object of providingcompounds which have an anti-inflammatory action and have an improvedaction.

This object is achieved by the compounds of the formula I. The inventionthus relates to compounds of the formula I

whereinR1 is chosen fromA) RO—, wherein R is chosen from:

-   -   a) C₁-C₆-alkyl, which is substituted by 1, 2 or 3 hydroxyl or        C₁-C₆-alkoxy groups;    -   b) C₁-C₆-alkyl, which is substituted by a saturated or        unsaturated, aromatic or non-aromatic heterocyclic radical        having 5 or 6 ring atoms, which contains 1, 2 or 3 hetero atoms        which are chosen independently of each other from O, N and S,        wherein the heterocyclic radical can optionally contain 1 or 2        hydroxy, C₁-C₆-alkoxy or C₁-C₆-alkyl substituents and can be        condensed with a phenyl ring or a saturated or unsaturated        carbocyclic radical having 5 or 6 ring atoms;    -   c) a non-aromatic heterocyclic radical having 5 or 6 ring atoms,        which contains 1 or 2 hetero atoms which are chosen        independently of each other from O and N;    -   d) C₁-C₆-alkyl;    -   e) H;    -   f) C₁-C₆-alkyl, which is substituted by NR6R7;    -   g) CF₃SO₂—;    -   h) C₁-C₆-alkylcarbonyloxy-C₁-C₆-alkyl; and    -   i) (C3-C7-cycloalkyl)-C₁-C₆-alkyl, which can optionally contain        1 or 2 hydroxy, C₁-C₆-alkoxy or C₁-C₆-alkyl substituents on the        cycloalkyl radical;

B) NR6R7;

C) tetrazolo; and

D) NR8CONR13R14;

-   -   R2 represents H or C₁-C₆-alkyl;    -   R3 is chosen from:

-   -   e) —NH—C₁-C₆-alkylene-NR6R7    -   f) tetrazolo;

-   R4 represents H, halogen or C₁-C₆-alkyl;

-   R5 represents H or C₁-C₆-alkyl, which is substituted by 1, 2 or 3    hydroxyl or C₁-C₆-alkoxy groups;

-   R6 and R7, which can be identical or different, represent H or    C₁-C₆-alkyl, which is substituted by 1, 2 or 3 hydroxyl or    C₁-C₆-alkoxy groups;

-   R8 represents H or C₁-C₆-alkyl;

-   R9, R10 and R11, which can be identical or different, are chosen    from:    -   a) H,    -   b) NH₂,    -   c) mono-C₁-C₆-alkylamino,    -   d) di-C₁-C₆-alkylamino,    -   e) C₁-C₆-alkyl,    -   f) C₁-C₆-alkoxy,    -   g) hydroxyl,    -   h) halogen,    -   i) C₁-C₆-alkyl, which is substituted by 1, 2 or 3 halogen atoms;    -   j) CONR6R7; and    -   k) NO₂;        R12 represents H or NH₂;        R13 and R14, which can be identical or different, represent H or        C₁-C₆-alkyl, or together with the nitrogen atom to which they        are bonded form a non-aromatic heterocyclic radical having 5 or        6 ring atoms, which contains 1 or 2 hetero atoms which are        chosen independently of each other from O and N;        and the optical isomers, physiologically acceptable salts and        solvates thereof.

The expression “alkyl” (also in combination with other groups, such asalkoxy, haloalkyl etc.) includes straight-chain and branched alkylgroups having preferably 1 to 6 or 1 to 4 carbon atoms, such as methyl,ethyl, n- and i-propyl, n-, i- and t-butyl, sec-butyl, n-pentyl andn-hexyl.

The expression “halogen” stands for a fluorine, chlorine, bromine oriodine atom, in particular for a fluorine or chlorine atom.

C₁-C₆-Alkoxy which is substituted by 1, 2 or 3 hydroxyl or C₁-C₆-alkoxygroups is preferably C₂-C₆-alkoxy, in particular 2-hydroxyethoxy,3-hydroxypropoxy, 2-hydroxypropoxy, 1,2-dihydroxyethoxy,2,3-dihydroxypropoxy or 2,3-dimethoxypropoxy.

A saturated non-aromatic heterocyclic radical is, in particular,pyrrolidinyl, piperidinyl, hydroxypiperidinyl, piperazinyl,tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl,2,2-dimethyldioxolanyl, dioxanyl, morpholinyl or thiomorpholinyl. Thepiperidinyl radical can be substituted by 1, 2, 3 or 4 C₁-C₄-alkylgroups, in particular methyl groups. A preferred piperidinyl radical is2,2,6,6-tetramethylpiperidinyl. The nitrogen-containing heterocyclicradicals can be bonded via a nitrogen atom or a carbon atom.

An unsaturated non-aromatic heterocyclic radical is, in particular,pyrrolinyl, di- or tetrahydropyridinyl.

An aromatic heterocyclic radical is, in particular, pyridyl, preferably3- or 4-pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, furyl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl or thecorresponding benzo derivatives thereof.

R1 preferably represents the abovementioned meanings Aa), Ab), Ac), Ad)and B). According to one embodiment, R1 is in position 7 (position 1with respect to X). According to a further embodiment, R1 is in position8 (position 2 with respect to X). According to a further embodiment, R1is in position 9 (position 3 with respect to X). Positions 7 and 8 andin particular position 7 are preferred.

R2 preferably represents H.

The radical R3 is preferably in position 3 (with respect to Y).According to one embodiment, R3 represents the abovementioned meaningsb), e) and g).

According to a further embodiment, R3 represents the abovementionedformula (b).

According to a further embodiment, R3 represents

wherein R8, R9, R10 and R11 have the meanings given above. R10 and R11are preferably in the 3- and 5-position.

According to a further embodiment, R3 represents

wherein R8, R9 and R10 have the meanings given above. R10 is preferablyin the 4-position.R4, R5, R6, R7 and R8 preferably represent H.R9, R10 and R11 preferably represent the abovementioned meanings a), b),e), f), g) and h), and in particular H, NH₂, C₁-C₆-alkoxy or halogen.R12 preferably represents H.

If R1 represents the meaning Ae), it is preferably a non-aromaticheterocyclic radical having 5 or 6 ring atoms, which contains 1 or 2oxygen hetero atoms, and in particular tetrahydropyranyloxy or2,2-dimethyldioxolanyl.

One embodiment of the invention are the compounds of the formula Ia:

wherein Y represents O or S and R1, R2, R3 and R4 have theabovementioned meanings.

A further embodiment are the compounds of the formula Iaa

wherein R1, R2, R9 and R10 have the meanings given above.

According to one embodiment, in the formulae Ia and Iaa R2 and R4represent H. According to one embodiment, R1 is in position 1 or 2(relative to the methylene group of the 7-membered ring) and R3 is inposition 2 (relative to Y). According to a further embodiment, R2 and R4represent H and R1 is in position 1 or 2 (relative to the methylenegroup of the 7-membered ring) and R3 is in position 2 (relative to Y).

A further embodiment are the compounds of the formulae Iab and Iac

wherein R1, R9 and R10 have the meanings given above.

A further embodiment of the invention are the compounds of the formulaIb

wherein X represents O or S and R1, R2, R3 and R4 have the meaningsgiven above.

A further embodiment are the compounds of the formula Iba:

According to one embodiment, in the formulae Ib and Iba R2 and R4represent H. According to one embodiment, R1 is in position 1 or 2(relative to X) and R3 is in position 2 (relative to the methylene groupof the 7-membered ring). According to a further embodiment, R2 and R4represent H and R1 is in position 1 or 2 (relative to X) and R3 is inposition 2 (relative to the methylene group of the 7-membered ring).

A further embodiment are the compounds of the formula Ibb

wherein X represents O or S and R1, R9 and R10 have the meanings givenabove.

A further embodiment are the compounds of the formula Ibc

wherein X represents O or S and R2, R9 and R10 have the meanings givenabove.

A further embodiment are the compounds of the formula Ic

wherein —X—Y— represents —CH₂—CH₂— or —CH═CH— and R1, R2, R3 and R4 havethe meanings given above.

A further embodiment are the compounds of the formula Ica:

wherein —X—Y— represents —CH₂—CH₂— or —CH═CH— and R1, R2, R9 and R10have the meanings given above.

According to one embodiment, in the formulae Ic and Ica R2 and R4represent H. According to one embodiment, R1 is in position 1 or 2(relative to X) and R3 is in position 2 (relative to Y). According to afurther embodiment, R2 and R4 represent H and R1 is in position 1 or 2(relative to X) and R3 is in position 2 (relative to Y).

A further embodiment are the compounds of the formulae Icb and Icc

wherein —X—Y— represents —CH₂—CH₂— or —CH═CH— and R1, R2, R9 and R10have the meanings given above.

The invention also includes the physiologically acceptable salts of thecompounds of the formula I. In the present case, these are, inparticular, the acid addition salts. Inorganic acids, such ashydrochloric acid, sulfuric acid or phosphoric acid, or organic acids,such as tartaric acid, citric acid, maleic acid, fumaric acid, malicacid, mandelic acid, ascorbic acid, gluconic acid, methanesulfonic acid,benzenesulfonic acid or toluenesulfonic acid and the like, are employedfor formation of the acid addition salts.

Where the compounds according to the invention have centers ofasymmetry, the invention likewise provides the racemates and theindividual optical isomers (enantiomers, diastereomers).

The invention also provides the solvates of the compounds of the formulaI or of the salts thereof, in particular the hydrates.

The preparation of the compounds of the formula I which are substitutedat position 7, wherein X—Y represents CH₂—CH₂ or CH═CH, is carried outby the processes explained by way of example in equations I to III.

Starting from 3-methoxybenzoic acid (1), a formyl group is introducedvia the phthalide (2). By means of a Wittig reaction, the unsaturatedcompound (5a) is obtained, which can be hydrogenated in the conventionalmanner, for example using a noble metal catalyst, such as Pt or Pd.Before the cyclization by Friedel-Crafts acylation, the amino group isprotected by a suitable protective group, which is removed after theFriedel-Crafts acylation. After reaction with an aryl halide, compound(10) is obtained.

Equation II shows an alternative process for the preparation of (10),with which the use of the protective group can be avoided:

The compounds (10) methoxy-substituted at position 7 can be convertedinto the hydroxy compounds (11) by ether cleavage, for example by meansof aqueous HBr, see equation III.

The hydroxyl group at position 7 allows further substitution, forexample via the Williams ether synthesis or the Mitsunobu reaction, seeequation IV:

The preparation of the compounds of the formula I which are substitutedat position 8 or 9, wherein X—Y represents CH₂—CH₂ or CH═CH, is carriedout by the processes explained by way of example in equations V to X.

Starting from methoxymethylbenzoic acid, a bromination is first carriedout with N-bromosuccinimide (NBS). The bromomethylmethoxybenzoic acid(6) formed is reacted with 3-chlorobenzaldehyde in a Wittig reaction togive chlorophenylvinylmethoxybenzoic acid (7). The subsequenthydrogenation of the chlorophenylvinylmethoxy-benzoic acid is carriedout in the conventional manner using noble metal catalysts, such asPd/BaSO₄ (substitution in position 8) or Pd/C (substitution in position9). The carboxylic acid (8) is converted into the acid chloride, forexample by reaction with thionyl chloride. The subsequent cyclization to(9) is carried out by Friedel-Crafts acylation with suitable Lewisacids, such as AlCl₃. Compound (10) is then obtained by ether cleavage,for example with aqueous hydrogen bromide.

Carboxylate is added to a cooled solution ofchlorohydroxydibenzodihydrodibenzosuberone, hydroxytetrahydropyran,triphenylphosphine and THF. The reaction is continued to the end at roomtemperature. The chlorine at position 2 can be substituted in accordancewith equation X.

The following compounds were obtained in this manner:

Compound of Example no. R₁ R₃ 71 (11h)

70 (15)

—Cl

A mixture of the phenolic compound, N-2-chloroethylmorpholine and K₂CO₃is stirred for several hours, with heating. After cooling, the desiredcompound is obtained in the conventional manner and the organic phase isseparated off, washed and concentrated. The chlorine at position 2 canbe substituted in accordance with equation X.

The following compounds were obtained in this manner:

Compounds in position 9 Compounds in position 8

Compound Compound of Example of Example no. R₁ R₃ no. R₁ R₃ 73 (11j)

56 (12e)

89 (16)

—Cl 90 (17)

—Cl

The following compounds were obtained in this manner:

Compounds in position 9 Compounds in position 8

Compound Compound of Example of Example no. R₁ R₃ no. R₁ R₃ 66 (11d)

51 (12a)

68 (11e)

53 (12b)

67 (11f)

52 (12c)

69 (11g)

54 (12d)

65 (13)

—Cl 87 (14)

—Cl

The mixture of chlorodihydrodibenzosuberenone, Pd(OAc)₂, phosphineligand (2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl),NaOtert-Bu, toluene, tert-BuOH and the amine R₃NH₂ is stirred atelevated temperatures for several hours. After cooling, the desiredproduct is obtained in the conventional manner.

The following compounds were obtained in this manner:

Compound of Example no. R₁ R₃ 63 (11a) —CH₃

64 (11b) —CH₃

62 (11c) —OH

The preparation of the compounds of the formula I which are substitutedat position 7, wherein one of the ring atoms X or Y represents CH₂, iscarried out by the process explained in equation XI.

After esterification of the starting compound 2-methyl-4-nitrobenzoicacid, bromination is carried out with N-bromosuccinimide (NBS) in theconventional manner. The brominated educt is reacted with the phenol inthe presence of potassium carbonate. After hydrolysis of the ester, forexample with KOH, cyclization is carried out, for example withpolyphosphoric acid in an organic solvent, such as sulfolane. The nitrogroup is then reduced to the amino group in the conventional manner, forexample with Sn/HCl. It is advisable to work at elevated temperatures,expediently at the boiling temperature of the solvent or under reflux.

The preparation of the compounds of the formula I wherein one of thering atoms X or Y represents SO or SO₂ is carried out by oxidation ofthe compounds wherein Y represents S in the conventional manner, forexample with per-compounds, such as m-chloroperbenzoic acid.

The compounds according to the invention show an action which isimmunomodulating and inhibits the release of TNF-α and IL-1β in vitroand in vivo. The compounds according to the invention are thereforesuitable for treatment of diseases related to a disturbance in theimmune system. They are suitable, for example, for treatment ofautoimmune diseases, cancer, rheumatic arthritis, gout, septic shock,osteoporosis, neuropathic pain, HIV propagation, HIV dementia, viralmyocarditis, insulin-dependent diabetes, periodontal diseases,restenosis, alopecia, T-cell depletion with HIV infections or AIDS,psoriasis, acute pancreatitis, rejection reactions with allogenictransplants, lung inflammation of allergic origin, arteriosclerosis,multiple sclerosis, cachexia, Alzheimer's disease, stroke, jaundice,colitis ulcerosa, Crohn's disease, inflammatory bowel disease (IBD),ischaemia, congestive cardiac insufficiency, pulmonary fibrosis,hepatitis, glioblastoma, Guillain-Barré syndrome, systemic lupuserythematosus, adult respiratory distress syndrome (ARDS) andrespiratory distress syndrome.

The compounds according to the invention can be administered either asindividual therapeutic active compounds or as mixtures with othertherapeutic active compounds. The compounds can be administered bythemselves, but in general they are dosed and administered in the formof pharmaceutical compositions, i.e. as mixtures of the active compoundswith suitable pharmaceutical carriers or diluents. The compounds orcompositions can be administered orally or parenterally, preferably theyare administered in oral dosage forms.

The nature of the pharmaceutical composition or carrier or of thediluent depends on the desired form of administration. Oral compositionsfor example can be in the form of tablets or capsules and can containconventional excipients, such as binders (e.g. syrup, acacia, gelatin,sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose,sugar, maize starch, calcium phosphate, sorbitol or glycine), lubricants(e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide),disintegrating agents (e.g. starch) or wetting agents (e.g. sodiumlauryl sulfate). Liquid oral preparations can be in the form of aqueousor oily suspensions, solutions, emulsions, syrups, elixirs or sprays andthe like. They can also be in the form of a dry powder, which isprepared for administration by reconstitution with water or anothersuitable carrier. Such liquid preparations can contain conventionaladditives, for example suspending agents, flavor substances, diluents oremulsifiers. Solutions or suspensions with conventional pharmaceuticalcarriers can be employed for parenteral administration.

The compounds or compositions according to the invention can beadministered to mammals (humans or animals) in a dose of from about 0.5mg to 100 mg per kg of body weight per day. They can be administered ina single dose or in several doses.

The action spectrum of the compounds as inhibitors of the release ofTNF-α and IL-1β was investigated with the aid of the test systems asdescribed by Donat C. and Laufer S. in Arch. Pharm. Pharm. Med. Chem.333, Suppl. 1, 1-40, 2000. The IC₅₀ values obtained were set in relationto the values for the compound SB-203580 of the formula

The numerical values given in the following table are therefore therelative activity, calculated from the ratio of IC₅₀ (SB-203580)/IC₅₀(test compound). The higher the numerical value, the more active thecompound. The compounds in which R1 represents H represent the prior artaccording to WO2006/120010.

TABLE Inhibition of p38 MAP kinase and TNF-α (I)

p38 Inhi- MAP bition of R1 R3 X Y kinase TNF-α H 2-[NH-(2-NH₂- CH₂ O0.23 phenyl)] 2-NH₂ 2-[NH-(2-NH₂- CH₂ O 0.93 phenyl)] 2-OCH₃2-[NH-(2-NH₂- CH₂ O 0.57 phenyl)] 2-(OCH₂CH₂- 2-[NH-(2-NH₂- CH₂ O 0.32morpholine) phenyl)] H 2-[NH-(2,4-di-F- CH₂ O 0.31 0.09 phenyl)]2-(NHCO- 2-[NH-(2,4-di-F- CH₂ O 0.51 morpholine) phenyl)] 2-(OCH₂CH₂-2-[NH-(2,4-di-F- CH₂ O 1.92 0.02 morpholine) phenyl)] 1-OCH₃2-[NH-(2,4-di-F- CH₂ O 1.11 0.04 phenyl)] 2-(OCH₂CH₂— 2-[NH-(2,4-di-F-CH₂ O 1.02 N(CH₃) phenyl)] H 2-[NH-(2-NH₂- CH₂ CH₂ 0.54 0.51 phenyl)]3-OCH₃ 2-[NH-(2-NH₂- CH₂ CH₂ 1.00 0.91 phenyl)] (S)-3-[OCH₂—2-[NH-(2-NH₂- CH₂ CH₂ 1.54 >5 CH(OH)—CH₂OH] phenyl)] (S)-3-(OCH₂-3,3-2-[NH-(2-NH₂- CH₂ CH₂ 1.31 >5 di-CH₃-2,4- phenyl)] dioxolane)3-(OCH₂-3,3-di- 2-[NH-(2-NH₂- CH₂ CH₂ 0.72 >5 CH₃-2,4- phenyl)]dioxolane) H 2-[NH-(2,4-di-F- CH₂ CH₂ 0.52 0.49 phenyl)] 1-OH2-[NH-(2,4-di-F- CH₂ CH₂ 2.26 0.06 phenyl)] 1-[OCH₂— 2-[NH-(2,4-di-F-CH₂ CH₂ 1.76 CH(OH)—CH₂OH] phenyl)] 1-(OCH₂CH₂- 2-[NH-(2,4-di-F- CH₂ CH₂1.26 morpholine) phenyl)] 2-OCH₃ 2-[NH-(2,4-di-F- CH₂ CH₂ 2.60 phenyl)]2-(OCH₂CH₂- 2-[NH-(2,4-di-F- CH₂ CH₂ 2.53 morpholine) phenyl)] 2-(OCH2—2-[NH-(2,4-di-F- CH₂ CH₂ 2.60 CH2OH) phenyl)] 3-OH 2-[NH-(2,4-di-F- CH₂CH₂ 2.03 1.80 phenyl)] 3-OCH₃ 2-[NH-(2,4-di-F- CH₂ CH₂ 1.59 0.70phenyl)] (S)-3-(OCH₂-3,3- 2-[NH-(2,4-di-F- CH₂ CH₂ 1.86 3.79 di-CH₃-2,4-phenyl)] dioxolane) 3-(O-tetrahydro- 2-[NH-(2,4-di-F- CH₂ CH₂ 0.74 1.98pyran-4-yl) phenyl)] (S)-3-(OCH₂-3,3- 2-[NH-(2,4-di-F- CH₂ CH₂ 1.04 >5di-CH₃-2,4- phenyl)] dioxolane) 3-(OCH₂—CH(OH) 2-[NH-(2,4-di-F- CH₂ CH₂3.00 4.98 phenyl)] 3-(OCH₂— 2-[NH-(2,4-di-F- CH₂ CH₂ 4.85 >5 CH₂CH₂OH)phenyl)] 3-(OCH₂-3,3-di- 2-[NH-(2,4-di-F- CH₂ CH₂ 0.32 3.75 CH₃-2,4-phenyl)] dioxolane) 3-(O—CH₂- 2-[NH-(2,4-di-F- CH₂ CH₂ 3.04 4.90tetrahydro-pyran- phenyl)] 4-yl) H 2-[NH-(2-NH₂-4F- CH₂ CH₂ 0.37 0.67phenyl)] 3-OCH₃ 2-[NH-(2-NH₂-4F- CH₂ CH₂ 0.92 0.73 phenyl)] H2-[NH-(2-NH₂-4F- CH₂ O 0.52 0.08 phenyl)] 2-NH₂ 2-[NH-(2-NH₂-4F- CH₂ O1.15 0.24 phenyl)] H 2-[NH-(2-OCH₃- CH₂ O 0.09 0.13 phenyl)] 2-NH₂2-[NH-(2-OCH₃- CH₂ O 0.14 0.04 phenyl)] 3-OCH₃ 2-[NH-(2-OCH₃- CH₂ CH₂0.11 0.18 phenyl)]

It can be seen that the compounds according to the invention have anexcellent activity and are superior to the compounds of WO 2006/120010.

The following examples illustrate the invention without limiting it.

Equipment and Methods

Melting points Büchi Melting Point B-545 (thermodynamic correction) NMRspectroscopy Bruker Avance 200 (200 MHz) IR spectroscopy Perkin-ElmerSpectrum One (ATR) GC-MS Hewlett Packard HP 6890 Series GC-SystemHewlett Packard HP 5973 Mass Selective Detector GC column: HP-5MS 5%phenylmethylsiloxane ESI-MS: 70 eV

GC Method:

Temperature [° C.] Migration time [min] 160 1 160 → 240 10 240 5 240 →270 10 270 35

Abbreviations: MeOH Methanol

NaOMe Sodium methylateKOtert-Bu Potassium tert-butylateTert-BuOH tert-Butanol

EtOH Ethanol DMF Dimethylformamide THF Tetrahydrofuran

MC Methylene chloridei. vac. in vacuoEA Ethyl acetate

General Method A

For the synthesis of the stilbenes by means of a Wittig reaction, thestated amount of triphenylphosphine is dissolved in MeOH. Whilestirring, the corresponding benzyl chloride is added dropwise and themixture is heated under reflux for 2 hours. The reaction mixture iscooled to 0° C. and the corresponding aldehyde is added. The statedamount of NaOMe solution is then added dropwise at 0° C. in the courseof approx. 45 min. When the dropwise addition has ended, the reactionmixture is subsequently stirred at 0° C. for 3 h and poured on to astirred mixture of 75 g of ice and 175 ml of water. The mixture isfiltered with suction, the residue on the filter is washed with approx.50 ml of water and the combined aqueous phases are washed several timeswith methylene chloride in vacuo. By acidification of the aqueous phase,the product is obtained in the form of a precipitate, which is filteredoff. Purification is carried out by recrystallization from MeOH/H₂O.

General Method B

For the synthesis of the ketones by means of Friedel-Crafts acylation,the stated amount of acid is suspended in methylene chloride and themixture is flushed with argon. After heating to the reflux temperature,a solution of thionyl chloride in 50 ml of methylene chloride is addeddropwise in the course of 1 hour, while stirring, and the mixture isstirred for a further hour. After cooling to room temperature, asuspension of AlCl₃ in methylene chloride is added dropwise in thecourse of 45 min and the reaction mixture is subsequently stirred atroom temperature for 30 min and poured on to a mixture of 30 g of iceand 50 ml of water, while stirring. The hydrolysis mixture is stirredfor approx. 30 min, the precipitate is filtered off and the two phasesof the filtrate are separated. The product is obtained by concentrationof the organic phase in vacuo. Purification is carried out byrecrystallization with MeOH.

General Method C

For the preparation of the test compounds, a mixture of aryl halide,amine, Pd(OAc)₂, phosphine ligand, KOtert-Bu, toluene and tert-BuOH isheated to 100° C. under argon and stirred at this temperature for thestated time. Thereafter, the mixture is cooled to room temperature,hydrolysis is carried out with 150 ml of H₂O, the mixture is extracted3× with 200 ml of diethyl ether each time and the organic phase isfiltered and concentrated in vacuo. Purification is carried out viaflash chromatography.

General Method D

SnCl₂×5 H₂O is added to a solution of the nitro compound in EtOH. Themixture is refluxed for 5 h. It is then cooled and rendered alkalinewith 20% strength NaOH. It is extracted 3× with 200 ml of ethyl acetateeach time and the organic phase is concentrated in vacuo.

General Method E

For the preparation of2-chloro-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one,0.57 mmol of2-chloro-7-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one isdissolved in 10 ml of anhydrous DMF, and 0.82 mmol of the correspondingα,β-isopropylideneglycerol γ-tosylate and 1.65 mmol of K₂CO₃ are added.The reaction mixture is stirred at 80° C. under an argon atmosphere for24 h. The reaction mixture is cooled to room temperature dissolved in 50ml of water and extracted with diethyl ether and the organic phase isconcentrated in vacuo. The product is obtained in the form of a paleyellow oil.

General Method F

A solution of 2 mmol of P(Ph)₃ in 10 ml of THF is added dropwise to asolution of 2 mmol of diisopropyl azodicarboxylate in 20 ml of THF at 0°C. and the mixture is stirred for 1 h. A solution of 2 mmol of2-chloro-7-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one and 2 mlof the corresponding alcohol in THF is then added dropwise and themixture is stirred at room temperature for 2 h. It is hydrolyzed withwater and extracted with ethyl acetate and the organic phase isconcentrated in vacuo. Purification is carried out on SiO₂ (hexane/ethylacetate 7+3).

General Method G

1.7 mmol of2-chloro-7-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 1.86 molof alkyl halide and 6.57 mmol of K₂CO₃ are dissolved in either DMF oracetonitrile and the solution is stirred at 80° C. for the stated time,cooled to room temperature and dissolved in diethyl ether and water. Theorganic phase is washed with water and alkali, dried over MgSO₄ andconcentrated in vacuo.

EXAMPLE 1 6-Methoxyphthalide (2)

A mixture of 20 g (131 mmol) of 3-methoxybenzoic acid, 13 ml (160 mmol)of 37% strength formalin soln., 16 ml (162 mmol) of 37% strength HCl and150 ml of 100% strength acetic acid is heated to 90° C., while stirring.After a clear solution has formed, the stirrer is switched off and themixture is left at this temperature for 14 hours. The acetic acid isstripped off at 80° C. in vacuo, the residue is taken up in 150 ml oftoluene and the mixture is concentrated to 80 ml. The 80° C. hotsolution is washed with 40 ml portions of 20% strength Na₂SO₄ solutionuntil the pH of the aqueous solution is alkaline, and is then washedwith 40 ml of H₂O. After addition of 6 ml of morpholine, the organicphase is stirred at 80° C. for 2 h and then washed with 50 ml portionsof 10% strength H₂SO₄ until the aqueous phase is acidic, and twice with50 ml of H₂O each time. For crystallization of the product, the mixtureis concentrated to 50 ml, a seed crystal is added if necessary, and themixture is stirred until it has cooled to room temperature. The productis obtained by filtering off in the form of white crystals.

Yield: 13.8 g (64%); m.p.: 107.6° C.

IR (ATR): 2945(C—H)_(aliph), 1745 (C═O), 1489, 1320, 1278, 1247, 1054,1017, 990, 9056, 769.

¹H-NMR (DMSO-d6) δ in ppm: 3.84 (s, 3H, —OCH₃), 5.33 (s, 2H, C³—H), 7.28(s, 1H, C⁷—H), 7.31 (d, J=8.3 Hz, C⁴—H), 7.56 (d, 1H, J=8.3 Hz, C⁵—H).

EXAMPLE 2 2-Formyl-5-methoxy-benzoic acid (3)

10 g (61 mmol) of 6-methoxyphthalide, 11.4 g (64.0 mmol) of NBS and 200ml of chlorobenzene are mixed, while stirring, the suspension is heatedto 85° C. and 2 ml of a solution of 100 mg of AIBN in 10 ml ofchlorobenzene are added. In the course of a few minutes, the temperaturerises to 110° C. and a red solution forms. After the rise in-temperaturehas subsided, the remaining 8 ml are added and the mixture is stirred at85° C. for 40 min. After cooling to 0° C., the succinimide which hasprecipitated out is filtered off and rinsed with chlorobenzene. Thefiltrate is concentrated until an oily residue forms, which is taken upin 10% strength NaOH solution, and the mixture is washed three timeswith 300 ml of methylene chloride each time. After acidification of theaqueous phase with concentrated HCl, the mixture is stirred at 0° C. for1 hour. The acid thereby precipitates out in the form of a whiteprecipitate, which is filtered off.

Yield: 9.6 g (87%); melting point: 166.2° C.

IR (ATR): 2903 (COOH), 2601 (C—H)_(aliph), 1703, 1586 (C═O), 1497, 1278,1210, 1187, 1142, 1072, 1025, 897, 823, 736.

H₁-NMR (DMSO-d6) δ in ppm: 3.64 (s, 3H, —OCH₃), 6.59 (s, 1H, —CHO),7.23-7.86 (m, 3H, C³—H, C⁴—H, C⁶—H). 10.3 (s, 1H, —COOH).

EXAMPLE 3 2-(3-Nitrophenethenyl)-5-methoxybenzoic acid (5a)

For the synthesis of compound 5a by method A, 15.3 g (0.058 mol) oftriphenylphosphine, in 100 ml of MeOH, 10.0 g (0.058 mol) of nitrobenzylchloride (dissolved in 50 ml of MeOH), 9.6 g (0.058 mol) of2-formyl-5-methoxybenzoic acid and 28.0 g (0.145 mol) of 28% strengthNaOMe solution are used. Yield: 13.5 g (78%); melting point: 174.7° C.

IR (ATR): 2838 (COOH), 2627 (C—H)_(aliph), 1687 (C═O), 1530, 1348, 1266,1237, 810, 734, 671.

H₁-NMR (DMSO-d6) δ in ppm: 3.80 (s, 3H, —OCH₃), 6.67 (d, 1H, J=12.1 Hz,CH═CH), 6.98-7.00 (m, 2H, C³H, C⁴—H, 7.12 (d, 1H, J=12.0 Hz, CH═CH),7.43-7.47 (m, 3H, C⁶—H,

—H,

—H), 7.88 (s, 1H,

—H), 7.98 (m, 1H,

—H).

EXAMPLE 4 2-(3-Chlorophenethenyl)-5-methoxybenzoic acid (5b)

For the synthesis of the compound 5b by method A, 15.3 g (0.058 mol) oftriphenylphosphine, in 100 ml of MeOH, 9.4 g (0.058 mol) of chlorobenzylchloride (dissolved in 50 ml of MeOH), 9.6 g (0.058 mol) of2-formyl-5-methoxybenzoic acid and 28.0 g (0.145 mol) of 28% strengthNaOMe solution are used. Yield: 6.7 g (40%); melting point: 142.3° C.

IR (ATR) 2835 (COOH), 2563 (C—H)_(aliph), 1681 (C═O), 1604, 1594, 1419,1265, 1251, 1218, 840, 779, 756.

H₁-NMR (DMSO-d6) δ in ppm: 3.79 (s, 3H, —OCH₃), 7.04 (d, 1H, J=16.3 Hz,CH═CH), 7.16 (dd, 1H, J₁=2.7 Hz, J₂=7.9 Hz), 7.31-7.36 (m, 2H,

—H,

—H), 7.41 (d, 1H, J=7.6, C⁴—H), 7.46-7.55 (m, 2H, C⁶—H,

—H), 7.76 (d, 1H, J=8.8 Hz, C³—H), 7.86 (d, 1H, J=16.4 Hz, CH═CH).

EXAMPLE 5 2-(3-Aminophenethyl)-5-methoxybenzoic acid (6a)

10.0 g (0.033 mol) of 2-(3-nitrophenethenyl)-5-methoxybenzoic acid aresuspended in 150 ml of EtOH and 100 mg of Pd/charcoal are added. Themixture is flushed with H₂ several times and stirred at room temperaturefor 72 hours. After filtering off the Pd/charcoal, the mixture isconcentrated in vacuo and the residue is recrystallized with MeOH/H₂O.

Yield: 8.5 g (95%); melting point 108.5° C.

H₁-NMR (DMSO-d6) δ in ppm: 2.61 (2H, m, —CH₂—CH₂—), 3.05 (m, 2H,—CH₂—CH₂), 3.75 (s, 3H, —OCH₃), 6.36-6.44 (m, 3H,

—H,

—H,

—H), 6.90 (t, 1H, J₁=7.6 Hz, J₂=7.7 Hz,

——H), 7.01 (d, 1H, J=8.5 Hz, C⁴—H), 7.20 (d, 1H, J=8.5 Hz, C³—H), 7.3(s, 1H, C⁶—H).

EXAMPLE 6 2-(3-Chlorophenethyl)-5-methoxybenzoic acid (6b)

5.0 g (0.017 mol) of 2-(3-chlorophenethenyl)-5-methoxybenzoic acid aredissolved in a mixture of 75 ml of ethyl acetate and 75 ml ofacetonitrile, and 100 mg of Pd/charcoal are added. The mixture isflushed with H₂ several times and stirred at room temperature for 5hours. After filtering off the Pd/charcoal, the mixture is concentratedin vacuo and the residue is recrystallized with MeOH/H₂O. Yield: 4.7 g(95%)

H₁-NMR (DMSO-d6) δ in ppm: 2.73-2.81 (m, 2H, —CH₂—CH₂—), 3.05-3.13 (m,2H, —CH₂—CH₂—), 3.75 (s, 3H, OCH₃), 6.99-7.35 (m, 6H, C³—H, C⁴—H, C⁶—H,

—H,

—H,

—H,

—H).

EXAMPLE 7 2-(3-Acetamidophenethyl)-5-methoxybenzoic acid (7a)

20 g (0.074 mol) of 2-aminophenethyl-5-methoxybenzoic acid are dissolvedin 50 ml of acetic anhydride and the solution is stirred at roomtemperature for 15 hours. Hydrolysis is carried out with 200 ml ofice-water and the mixture is extracted several times with in each case3×200 ml of ethyl acetate. After concentrating the organic phase invacuo, a yellow oil is obtained, from which the product is obtained byrecrystallization with MeOH/H₂O.

Yield: 16.4 g (0.058 mol) (79.0%); melting point: 145.6° C.

IR (ATR) 3265-2933, 2562 (C—H)_(aliph), 1622, 1693, 1593, 1567, 1437,1420, 1289, 1235, 789, 747.

H₁-NMR (DMSO-d6) δ in ppm: 2.01 (s, 3H, —CO—CH₃), 2.74 (m, 2H,—CH₂—CH₂), 3.08 (m, 2H, —CH₂—CH₂), 3.74 (s, 3H, —OCH₃), 6.89 (d, 1H,J=7.6 Hz,

—H), 6.95 (d, 1H, J=8.5 Hz,

—H), 7.12-7.20 (m, 2H,

—H,

—H), 7.28 (d, 1H, J=2.8 Hz, C⁴—H), 7.44-7.46 (m, 2H, C³—H, C⁶—H), 9.89(s, 1H, —NH—).

EXAMPLE 8 2-Nitro-7-methoxydibenzosuberenone (8d)

For the preparation of 2-nitro-7-methoxydibenzosuberenone by method B,5.1 g (0.019 mol) of 2-(3-nitrophenylethenyl)-5-methoxybenzoic acid, 150ml of methylene chloride, 2.42 g (0.02 mol) of thionyl chloride and 3.33g (0.025 mol) of AlCl₃ are used.

Yield: 58%; melting point 163.7° C.

IR (ATR) 3093-3005 (C—H)_(arom), 2921-2838, 1703 (C═O), 1521, 1482,1431, 1347, 1290, 1223, 1257, 1019, 872, 806, 730, 674.

H₁-NMR (DMSO-d6) δ in ppm: 3.81 (s, 3H, —OCH₃), 6.92 (dd, 1H, J₁=2.4 Hz,J₂=8.0 Hz), 7.04 (d. 1H, J=2.5, C⁸—H), 7.21 (d, 1H, J=7.9, —CH═CH—),7.70 (d, 1H, J=8.0, C³—H), 8.13-8.24 (m, 2H, C²—H, C⁴—H), 8.34 (s, 1H,C¹⁰—H), 8.67 (t, 1H, J=2.0 Hz, C⁷—H).

EXAMPLE 9 2-Chloro-7-methoxysuberenone (8c)

For the preparation of compound 8c by method B, 5.5 g (0.019 mol) of2-(3-chlorophenylethenyl)-5-methoxybenzoic acid, 150 ml of methylenechloride, 2.42 g (0.02 mol) of thionyl chloride and 3.33 g (0.025 mol)of AlCl₃ are used. M.p. 133.0° C.; yield: 4.8 g (93%)

IR (ATR) 2923-2843 (C—H)_(aliph), 1636, 1605, 1583 (C═O), 1556, 1503,1298, 1245, 1225, 972, 878, 863, 835, 786.

H₁-NMR (DMSO-d6) δ in ppm: 3.89 (s, 3H, —OCH₃), 7.06 (d, 1H, J=12.1 Hz,—CH═CH—), 7.25 (d, 1H, J=12.1 Hz, —CH═CH—), 7.37 (dd, 1H, J₁=2.9 Hz,J₂=8.5 Hz, C³—H), 7.35-7.40 (m, 2H, C²—H, C¹⁰—H, 7.72 (d, 1H, J=8.7 Hz,C⁸—H), 7.85 (d, 1H, J=2.2 Hz, C⁴—H), 8.11 (d, 1H, J=8.6 Hz, C⁷—H).

EXAMPLE 10 2-Acetamido-7-methoxydibenzosuberone (8a)

For the preparation of compound 8a by method B, 6.0 g (0.019 mol) of2-(3-acetamidophenethyl)-5-methoxybenzoic acid, 150 ml of methylenechloride, 2.42 g (0.02 mol) of thionyl chloride and 6.66 g (0.05 mol) ofAlCl₃ are used. Yield 4.66 g (83%

MS m/z (%): 295 (100, M⁺), 253 (60, M⁺-COCH₃), 238 (12, 253-CH₃), 224(36, 238-NH), 210 (10), 194 (10), 180 (9), 165 (14), 152 (8).

H₁-NMR 2.07 (s, 3H, —COCH₃), 3.05 (s, 4H, —CH₂—CH₂), 3.75 (s, 3H,—OCH₃), 7.05 (d, 1H, J=8.4 Hz, C⁸—H), 7.22 (d, 1H, J=8.4 Hz, C⁹—H), 7.38(s, 1H, C⁵—H), 7.52-7.56 (m, 2H, C¹—H, C³—H), 7.92 (d, 1H, J=9.3 Hz,C⁴—H), 10.22 (s, 1H, —NH—).

EXAMPLE 11 2-Chloro-7-methoxydibenzodibenzosuberone (8b)

For the preparation of compound 8b by method B, 5.5 g (0.019 mol) of2-(3-chlorophenylethyl)-5-methoxybenzoic acid, 150 ml of methylenechloride, 2.42 g (0.02 mol) of thionyl chloride and 3.33 g (0.025 mol)of AlCl₃ are used. Yield 58%

MS m/z (%): 274/272 (35/100, M⁺), 259/257 ((5/17, M⁺-CH₃), 243, 241(19/21, M⁺-OCH₃), 208 (29), 194 (17), 178 (23, 208-CO), 165 (49).

H₁-NMR (DMSO-d6) δ in ppm: 3.09 (s, 4H, —CH₂—CH₂), 3.77 (s, 3H, —OCH₃),7.06 (dd, 1H, J₁=2.8 Hz, J₂=8.4 Hz, C⁸—H), 7.25 (d, 1H, J=8.4 Hz, C³—H),7.38-7.45 (m, 3H, C¹—H, C⁶—H, C⁹—H), 7.85 (d, 1H, J=8.3, C⁴—H).

EXAMPLE 12 2-Amino-7-methoxydibenzosuberone (9a)

4.0 g (0.0135 mol) of 2-acetamido-7-methoxydibenzosuberone are suspendedin 100 ml of 20% strength HCl and the reaction mixture is heated underreflux for 5 hours.

On cooling, a precipitate arises, which is filtered off. After drying invacuo, a sand-colored powder is obtained.

Yield: 1.85 g (0.0073 mol) (54.0%; melting point: 185.3° C.

MS m/z (%): 253 (100, M⁺), 238 (51, M⁺-CH₃), 224 (41, 238-NH), 210 (14),194 (12), 180 (13), 165 (13), 152 (6).

H₁-NMR 2.96 (s, 4H, —CH₂—CH₂), 3.75 (s, 3H, —OCH₃), 6.06 (s, 2H, —NH₂),6.34 (s, 1H, C¹—H), 6.49 (d, 1H, J=8.7 Hz, C³—H), 7.00 (d, 1H, J=8.3 Hz,C⁸—H), 7.19 (d, 1H, J=8.3 Hz, C⁹—H), 7.36 (s, 1H, C⁶—H), 7.87 (d, 1H,J=8.7 Hz, C⁴—H).

EXAMPLE 13 2-Chloro-7-hydroxydibenzosuberone (12)

0.13 ml (1.34 mmol) of boron tribromide is added dropwise to a solutionof 1.0 g (2.67 mmol) of 2-chloro-7-methoxydibenzosuberone in 10 ml of MCunder an argon inert gas atmosphere at room temperature. The reactionmixture is stirred at room temperature for 6 h, 20 ml of water are thenadded and the org. phase is concentrated in vacuo. The product isobtained in the form of an orange solid.

Yield: 0.66 g (95%); melting point: 191.6° C.

IR (ATR) 2926, 1589 (C═O), 1561, 1459, 1422, 1363, 1312, 1160, 1080,1006, 837, 798.

H₁-NMR (DMSO-d6) δ in ppm: 3.05 (dd, 4H, J₁=9.0, J₂=13.5, —CH₂—CH₂—),6.91 (d, 1H, J=8.2, C⁸—H), 7.13 (d, 1H, J=8.3, C⁹—H), 7.30-7.80 (m, 3H,C¹—H, C³—H, C⁶—H), 7.82 (d, 1H, J=9.1, C⁴—H).

¹³C-NMR (DMSO-d6) δ in ppm: 33.4 (C¹¹), 34.4 (C¹⁰), 116.2 (C⁶), 120.7(C⁸), 126.9 (C³), 129.3 (C¹), 131.5 (C⁹), 132.5 (C⁴), 133.1 (C^(4a)),137.1 (C^(5a)), 137.3 (C^(9a)), 138.5 (C²), 144.7 (C^(11a)), 156.1 (C⁷),193.5 (C⁵).

EXAMPLE 142-Chloro-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(13a)

The preparation of the title compound is carried out by method E. Yield:89%

C₂₁H₂₁ClO₄ (Mr=372.85)

MS m/z (%): 374/372 (15/43, M⁺), 359/357 (6/17), 299/297 (26/76),273/271 (5/13), 260/258 (4/10), 194 (11), 178 (24), 165 (37), 145 (24),115 (46), 101 (100), 73 (16), 59 (16).

¹H-NMR (DMSO-d6) δ in ppm: 1.29 (s, 3H, —CH₃), 1.34 (s, 3H, —CH₃), 3.06(s, 4H, —CH₂—CH₂—), 3.73-3.80 (m, 1H, —OCH₂—), 4.03-4.12 (m, 3H, —CH₂O—,—OCH₂—), 4.37-4.42 (m, 1H, —CH—), 7.13 (d, 1H, J=8.3, C⁸—H), 7.27 (d,1H, J=8.4, C⁹—H), 7.39-7.47 (m, 3H, C¹—H, C³—H, C⁶—H), 7.85 (d, 1H,J=8.3, C⁴—H).

¹³C-NMR (DMSO-d6) δ in ppm: 25.8 (—CH₃), 26.9 (—CH₃), 33.3 (C¹¹), 34.4(C¹⁰), 66.0 (—OCH₂—), 69.3 (—CH₂O—), 74.0 (—CH—), 115.0 (C⁶), 120.3(C⁸), 127.0 (C³), 129.5 (C¹), 131.6 (C⁹), 132.6 (C⁴), 135.1 (C^(4a)),136.9 (C^(5a)), 137.5 (C^(9a)), 138.6 (C²), 144.8 (C^(11a)), 157.3 (C⁷),193.2 (C⁵).

EXAMPLE 152-Chloro-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(13b)

The preparation of the title compound is carried out by method E. Yield:91%

C₂₁H₂₁ClO₄ (Mr=372.85); GC 24.6 min

MS m/z (%): 374/372 (16/45, M⁺), 359/357 (6/17), 299/297 (26/76),273/271 (5/13), 260/258 (4/11), 194 (12), 178 (26), 165 (39), 145 (25),115 (46), 101 (100), 73 (14), 59 (14).

¹H-NMR (DMSO-d6) δ in ppm: 1.29 (s, 3H, —CH₃), 1.34 (s, 3H, —CH₃), 3.10(s, 4H, —CH₂—CH₂—), 3.72-3.80 (m, 1H, —CH₂O—), 4.03-4.09 (m, 3H, —CH₂O—,—OCH₂—), 4.31-4.46 (m, 1H, —CH—), 7.13 (d, 1H, J=8.6 C⁸—H), 7.27 (d, 1H,J=8.5, C⁹—H), 7.39-7.49 (m, 3H, C¹—H, C³—H, C⁶—H), 7.85 (d, 1H, J=7.4,C⁴—H).

¹³C-NMR (DMSO-d6) δ in ppm: 25.7 (—CH₃), 26.9 (—CH₃), 33.3 (C¹¹), 34.3(C¹⁰), 660 (—CH₂O—), 69.3 (—OCH₂—), 74.0 (—CH—), 115.0 (C⁶), 120.2 (C⁸),127.0 (C³), 129.5 (C¹), 131.6 (C⁹), 132.6 (C⁴), 135.1 (C^(4a)), 136.9(C^(5a)), 137.5 (C^(9a)), 138.6 (C²), 144.7 (C^(11a)), 157.3 (C⁷), 193.1(C⁵).

EXAMPLE 162-Chloro-7-(3-acetoxypropoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(13h)

The preparation of the title compound is carried out by method G using3-iodopropyl acetate as the educt in DMF as the solvent. Yield: 87%

C₂₀H1₉ClO₄(Mr=358.83); GC 24.2 min

MS m/z (%): 360/358 (2/6, M⁺), 259/257 (2/5, M⁺-acetoxypropyl), 243/241(2/2, M⁺-acetoxypropoxy), 194 (9, 243/241-Cl), 178 (6), 165 (17), 101(100, acetoxypropyl), 73 (11).

¹H-NMR (DMSO-d6) δ in ppm: 1.96-2.08 (m, 5H, CH₃—Ac, —CH₂—), 3.04-3.13(m, 4H, —CH₂—CH₂—), 4.01-4.18 (m, 4H, —OCH₂—, —CH₂O—), 7.10 (d, 1H,J=8.3, C⁸—H), 7.25 (d, 1H, J=8.4, C⁹—H), 7.30-7.45 (m, 3H, C¹—H, C³—H,C⁶—H), 7.57 (d, 1H, J=8.3, C⁴—H).

¹³C-NMR (DMSO-d6) δ in ppm: 21.0 (CH₃Ac—), 28.4 (—CH₂—), 33.6 (C¹¹),34.3 (C¹⁰), 61.1 (AcO—CH₂ —), 64.8 (—OCH₂), 114.9 (C⁶), 120.3 (C⁸),127.6 (C³), 130.3 (C¹), 131.6 (C⁹), 132.6 (C⁴), 135.0 (C^(4a)), 136.9(C^(5a)), 137.5 (C^(9a)), 138.5 (C²), 144.7 (C^(11a)), 157.3 (C⁷), 170.7(C═O), 193.1 (C⁵).

EXAMPLE 172-Chloro-7-(3-acetoxyethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(13g)

The preparation of the title compound is carried out by method G using3-iodoethyl acetate as the educt and DMF as the solvent. Yield: 78%

C₁₉H₁₇ClO₄ (Mr=344.80); GC 21.1 min

MS m/z (%): 346/344 (2/4, M⁺), 194 (5, 241/243-Cl), 178 (8), 165 (11),87 (100, acetoxyethyl).

¹H-NMR (DMSO-d6) δ in ppm: 2.03 (s, 3H, —COCH₃), 3.10 (s, 4H,—CH₂—CH₂—), 4.19-4.23 (m, 2H, —OCH₂—), 4.30-4.35 (m, 2H, —CH₂—O—);7.11-7.48 (m, 5H, C¹—H, C³—H, C⁶—H, C⁸—H, C⁹—H), 7.86 (d, 1H, J=8.3,C⁴—H).

¹³C-NMR (DMSO-d6) δ in ppm: 21.0 (CH₃—CO—), 33.3 (C¹¹), 34.3 (C¹⁰), 62.8(AcO—CH₂ —), 66.4 (—CH₂O—), 115.0 (C⁶), 120.3 (C⁸), 127.0 (C³), 129.5(C¹), 131.6 (C⁹), 132.6 (C⁴), 135.2 (C^(11a)), 136.9 (C^(5a)), 137.5(C^(9a)), 138.6 (C²), 144.8 (C^(4a)), 157.1 C⁷), 170.7 (C═O), 193.1(C⁵).

EXAMPLE 182-Chloro-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(13c)

The preparation of the title compound is carried out by method G using2-chloroethylmorpholine hydrochloride as the educt in acetonitrile asthe solvent.

C₂₁H₂₂ClNO₃ (Mr=371.87); GC 32.7 min

MS m/z (%): 373/371 (1/2, M⁺), 330/328 (2/6), 286/284 (2/6,M⁺-morpholin-4-yl), 178 (6), 165 (4) 100 (100, morphin-4-yl-methyl).

¹H-NMR (DMSO-d6) δ in ppm: 3.11 (s, 4H, —CH₂—CH₂), 3.20-3.53 (m, 6H,—N—CH₂, —CH₂—N—CH₂—), 3.79-4.06 (m, 4H, —CH₂—O—CH₂—), 4.47-4.50 (m, 2H,(—OCH₂—), 7.19 (d, 1H, J=8.3, C⁸—H), 7.32 (d, 1H, J=8.4, C⁹—H),7.40-7.47 (m, 3H, C¹—H, C³—H, C⁶—H), 7.86 (d, 1H, J=8.4, C⁴—H), 11.57(s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.3 (C¹¹), 34.4 (C¹⁰), 57.0 (—CH₂ —O—CH₂—), 60.1 (—N—CH₂—), 65.5 (—OCH₂—), 66.1 (—CH₂ —O—CH₂ ), 115.1 (C⁶),120.3 (C⁸), 127.0 (C³), 129.5 (C¹), 131.6 (C⁹), 132.6 (C⁴), 135.0(C^(4a)), 136.9 (C^(5a)), 137.5 (C^(9a)), 138.6 (C²), 144.7 (C^(11a)),157.2 (C⁷), 193.2 (C⁵).

EXAMPLE 192-Chloro-7-(2-tetrahydropyran-4-yl-oxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(13i)

The preparation of the title compound is carried out by method F. Yield:46%

C₂₀H₁₉ClN₃ (Mr=342.83)

¹H-NMR (DMSO-d6) δ in ppm: 1.54-1.61 (m, 2H, —CH₂—), 1.91-1.98 (m, 2H,—CH₂—), 3.06-3.16 (m, 4H, —CH₂—CH₂—), 3.42-3.54 (m, 2H, —CH₂O—),3.78-3.86 (m, 2H, —CH₂O—), 4.56-4.62 (m, 1H, —CH—), 7.16 (d, 1H, J=8.4,C⁸—H), 7.27 (d, J=8.4, C⁹—H), 7.38-7.48 (m, 3H, C¹—H, C³—H, C⁶—H), 7.86(d, 1H, J=8.4 (C⁴—H).

EXAMPLE 20 2-(2-Aminoanilino)-7-methoxydibenzosuberone (10a)

For the preparation of compound 10a by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 1.0 (9.2 mmol) g of1,2-phenylenediamine, 0.05 g of Pd(OAc)₂, 0.10 g of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Yield: 0.48g (78%); m.p.: 106.5° C.

C₂₂H₂₀N₂O₂ (Mr=344.42); GC 49.4 min

MS m/z (%): 344 (100, M⁺), 329 (8), 315 (6), 301 (5), 195 (7), 165 (6),107 (9).

IR 3418-3343 (C—H)_(arom), 3320 (N—H), 2976-2939 (C—H)_(aliph), 1546(C═O), 1516, 1494, 1323, 1284, 1147, 1026, 828, 751, 740.

¹H-NMR (DMSO-d6) δ in ppm: 2.96 (s, 4H, —CH₂—CH₂), 3.76 (s, 3H, —OCH₃),4.84 (s, 2H, —NH₂), 6.46 (s, 1H, C¹—H), 6.54-6.64 (m, 2H,

—H,

—H), 4.78 (d, 1H, J=7.8 Hz,

—H), 6.91-7.04 (m, 3H, C³—H, C⁵—H, C⁸—H), 7.20 (d, 1H, J=8.3 Hz, C⁹—H),7.39 (s, 1H, C⁶—H), 7.92-7.97 (m, 2H, C⁴—H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.6 (C¹¹), 55.5 (—OCH₃), 112.1(C⁶), 113.1 (C³), 114.8 (C¹), 115.8 (C^(3′)), 116.8 (

), 118.3 (C⁸), 125.2 (

), 126.2 (

), 126.3 (

), 126.4 (C^(4a)), 130.4 (C⁹), 133.9 (C^(5a)), 134.5 (C⁴), 140.3(C^(9a)), 144.0 (

), 145.7 (C^(11a)), 151.1 (C²). 158.0 (C⁷), 190.3 (C⁵).

EXAMPLE 21 2-(2-Amino-4-fluoroanilino)-7-methoxydibenzosuberone (10b)

For the preparation of compound 10b by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.3 g (1.9 mmol) of2-nitro-4-fluoroaniline, 0.05 g of Pd(OAc)₂, 0.10 g of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Purificationof the nitro compound is carried out by recrystallization with MeOH.Without further purification, 0.5 g of the nitro compound, 2.9 g ofZnCl₂×2 H₂O in 20 ml EtOH are reduced by method D. Yield: 0.42 g (65%);m.p.: 72.2° C.

C₂₂H₁₉FN₂O₂ (Mr=362.41); GC 54.1 min

MS m/z (%): 362 (100, M⁺), 247 (7), 125 (14).

IR (ATR) 3353 (N—H), 2941-2834 (C−H)_(aliph), 1622, 1567 (C═O), 1508,1324, 1273, 1162, 839, 784.

¹H-NMR (DMSO-d6) δ in ppm: 2.49 (s, 4H, —CH₂—CH₂), 3.76 (s, 3H, —OCH₃),5.25 (s, 2H, —NH₂), 6.30-6.38 (m, 2H,

—H,

—H), 6.51-6.58 (m, 2H, C³—H,

—H), 7.94-7.05 (m, 2H, C¹—H, C⁸—H), 7.21 (d, 1H, J=8.3 Hz, C⁹—H), 7.38(s, 1H, C⁶—H) 7.89 (s, 1H, —NH—), 7.93 (d, 1H, C⁴—H).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.5 (C¹¹), 55.5 (—OCH₃), 101.4(d, J=25.5 Hz,

), 102.5 (d, J=22.6 Hz,

), 111.9 (C⁶), 112.9 (C³), 114.8 (C¹), 118.4 (C⁸), 121.3 (d, J=2.3 Hz,

), 126.2 (C^(4a)), 128.4 (d, J=20.8 Hz,

), 130.4 (C⁹), 134.0 (C^(5a)), 134.5 (C⁴), 140.3 (C^(9a)), 145.8(C^(11a)), 146.5 (d, J=12.0 Hz,

), 151.5 (C²), 158.0 (C⁷), 161.2 (d, J=238.6 Hz,

), 190.2 (C⁵).

EXAMPLE 22 2-(2,4-Difluoroanilino)-7-methoxydibenzosuberone (10c)

For the preparation of compound 10c by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.25 g (1.9 mmol) of2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol)of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Yield: 0.57g (87%);

m.p.: 123-126° C. (decomposition); C₂₂H₁₇F₂NO₂ (Mr=365.38); GC 31.4 min

MS m/z (%): 365 (100, M⁺), 350 (7, M⁺-CH₃), 337 (11), 322 (6), 237 (4,M⁺-2-NH₂, 4-F-aniline), 208 (15), 194 (5), 178 (6), 165 (15), 152 (5).

IR (ATR) 3327 (N—H), 3074 (C—H)_(arom), 2941-2842 (C—H)_(aliph), 1338,1551 (C═O), 1525, 1498, 1325, 1281, 1238, 854, 832, 786.

¹H-NMR (DMSO-d6) δ in ppm: 2.99 (s, 4H, —CH₂—CH₂), 3.76 8s, 3H, —OCH₃),6.61 (s, 1H, C¹—H), 6.74 (d, 1H, J=8.7 Hz, C³—H), 7.00-7.47 (m, 6H,C⁶—H, C⁸—H, C⁹—H,

—H,

—H,

—H), 7.95 (d, 1H, J=8.8 Hz, C⁴—H), 8.55 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 36.2 (C¹⁰), 38.6 (C¹¹), 55.5 (—OCH₃), 105.3(dd, J=26.7 Hz,

), 112.2 (d, J=22.1 Hz,

), 112.6 (C⁶), 113.9 (C³), 114.7 (C¹), 118.6 (C⁸), 125.3 (d, J=12.2 Hz,

), 126.4 (d, J=9.7 Hz,

), 127.7 (C^(4a)), 130.6 (C⁹), 133.8 (C^(5a)), 134.6 (C⁴), 140.0(C^(9a)), 145.7 (C^(11a)), 149.4 (C²), 154.9 (d, J=143.5 Hz,

), 158.1 (C⁷), 159.8 (d, J=138.2 Hz,

), 190.8 (C⁵).

EXAMPLE 23 2-(2-Chloro-4-fluoroanilino)-7-methoxydibenzosuberone (10d)

C₂₂H₁₇ClFNO₂ (Mr=381.84)

For the preparation of compound 10d by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.27 g (1.9 mmol) of 2-chloro,4-fluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Yield: 0.24g (35%);

m.p.: 110.2° C.; GC 38.4 min

MS m/z (%): 385/383 (36/100, M⁺), 368/366 (2/6, M⁺-CH₃), 354/352 (4/9),340/338 (2/4), 274/272 (2/6), 237 (4, M⁺-2-Cl, 4-F-aniline), 208 (14),194 (5), 178 (6, 208-CO), 165 (13), 151 (4), 136 (6).

IR (ATR) 3336 (N—H), 3070 (C—H)_(arom), 2939-2835 (C—H)_(aliph), 1602,1554 (C═O), 1520, 1484, 1282, 1255, 1235, 863, 818, 785.

¹H-NMR (DMSO-d6) δ in ppm: 3.00 (s, 4H, —CH₂—CH₂—), 3.77 (s, 3H, —OCH₃),6.60 (s, 1H, C¹—H), 6.72 (d, 1H, J=8.8 Hz, C³—H), 7.03 (d, 1H, J=5.6 Hz,

—H), 7.18-7.57 (m, 5H, C⁶—H, C⁸—H, C⁹—H,

—H,

—H), 7.94 d, 1H, J=8.7 Hz, C⁴—H), 8.46 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.5 (C¹²), 36.2 (C¹¹), 55.5 (OCH₃), 112.8(C⁶), 114.1 (C³), 114.6 (C¹), 115.6 (

), 117.7 (

), 118.6 (C⁸), 127.3 (

), 127.8 (C⁴), 129.4 (

), 130.6 (C⁹), 133.7 (C^(5a)), 134.7 (C⁴), 140.0 (C^(9a)), 145.7(C^(11a)), 149.5 (C²), 158.1 (C⁷), 158.9 (

), 190.8 (C⁵).

EXAMPLE 24 2-(2,4,5-Trifluoroanilino)-7-methoxydibenzosuberone (10e)

C₂₂H₁₆F₃NO₂ (Mr=383.37)

For the preparation of compound 10e by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.27 g (1.8 mmol) of 2-, 4-,5-trifluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol)of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Yield: 0.30g (43%);

m.p.: 132.1° C.; GC 30.0 min

MS m/z (%): 383 (100, M⁺), 368 (8, M⁺-CH₃), 355 (11), 340 (7), 237 (4,M⁺-2,3,4-trifluoroaniline), 208 (13), 194 (5), 178 (8), 165 (13).

IR (ATR) 3337 (N—H), 3298-3016 (C—H)_(arom), 2912-2846 (C—H)_(aliph),1582, 1567, 1518 (C═O), 1286, 1273, 1221, 1161, 856, 832, 808.

¹H-NMR (DMSO-d6) δ in ppm: 3.01 (s, 4H, —CH₂—CH₂), 3.76 (s, 3H, —OCH₃),6.72 (s, 1H, C¹—H), 6.82-7.05 (m, 2H,

—H,

—H), 7.21 (d, 1H, J=8.3 Hz, C³—H), 7.38-7.65 (m, 2H, C⁸—H, C⁹—H), 7.98(d, 1H, J=7.98 Hz, C²—H), 8.65 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.5 (C¹⁰), 36.1 (C¹¹), 55.5 (—OCH₃),106.4-107.4 (m,

), 111.9-112.3 (m,

), 113.3 (C⁶), 114.6 (C³), 114.7 (C¹), 118.7 (C⁸), 125.6-126.2 (m,

), 126.2 (C^(4a)), 128.6 (C⁹), 130.6 (C^(5a)), 133.6 (C⁴), 134.6(C^(9a)), 142.6-147.9 (m,

), 143.6-148.9 (m,

), 145.5 (C^(11a)), 148.3 (C²), 148.3-153.3 (m,

), 158.1 (C⁷), 191.1 (C⁵).

EXAMPLE 25 2-(2-Trifluoromethylanilino)-7-methoxydibenzosuberone (10f)

For the preparation of compound 10f by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.3 g (1.9 mmol) of2-aminotrifluoride, 0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol)of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Yield: 0.23g (32%);

m.p.: 152.5° C.;

C₂₃H₁₈F₃NO₂ (Mr=397.40); GC 30.3 min

MS m/z (%): 397 (100, M⁺), 282 (7, M⁺-CH₃), 368 (12), 354 (6), 237 (5,M⁺-2-CF₃-aniline), 208 (12), 194 (5),178 (6), 165 (14).

IR (ATR) 3319 (N—H), 3072-3007 (C—H)_(arom), 2958-2836 (C—H)_(aliph),1550 (C═O), 1460, 1353, 1323, 1285, 1264, 1111, 1091, 1050, 692.

¹H-NMR (DMSO-d6) δ in ppm: 3.02 (s, 4H, —CH₂—CH₂—), 3.76 (s, 3H, —OCH₃),6.91 (s, 1H, C¹—H), 7.01-7.06 (m, 2H, C³—H,

—H), 7.20-7.25 (m, 2H,

—H,

—H), 7.37-7.39 (m, 2H, C⁸—H,

—H), 7.47-7.52 (m, 2H, C⁶—H, C⁹—H), 7.98 (d, 1H, J=8.7 Hz, C⁴—H), 9.10(s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.5 (C¹⁰), 36.1 (C¹¹), 55.5 (—OCH₃), 114.0(C⁶), 114.5 (C³), 114.9-117.9 (m,

), 115.1 (C¹), 118.7 (

), 121.7 (C^(4a)), 127.1 (C¹¹), 129.1 (

), 129.1-132.6 (m, —CF₃), 130.7 (C⁹), 133.7 (C^(5a)), 134.6 (C⁴), 139.9(C^(9a)), 142.7 (

), 145.7 (C^(11a)), 147.3 (C²), 158.1 (C⁷), 191.2 (C⁵).

EXAMPLE 26 2-(Anilino)-7-methoxydibenzosuberone (10g)

For the preparation of compound 10 g by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.2 g (2.1 mmol) of aniline, 0.05 g(0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used.Yield: 0.27 g (46%);

m.p.: 123.5° C.; C₂₂H₁₉NO₂ (Mr=329.40); GC 35.1 min

MS m/z (%): 329 (100, M⁺), 314 (6, M⁺-CH₃), 300 (11), 286 (5), 270 (3),254 (3), 237 (2,M⁺-aniline), 208 (10), 194 (4), 180 (4), 165 (11).

IR (ATR) 3329 (N—H), 2992-2853 (C—H)_(aliph), 1560 (C═O), 1520, 1494,1319, 1280, 1262, 1240, 1035, 817, 742.

¹H-NMR (DMSO-d6) δ in ppm: 2.99 (s, 4H, —CH₂—CH₂), 3.75 (s, 3H, —OCH₃),6.93-7.05 (m, 3H, C³—H,

—H,

—H), 7.16-7.37 (m, 5H, C⁶—H, C⁸—H, C⁹—H,

—H,

—H), 7.95 (d, 1H, J=8.7 Hz, C⁴—H), 8.81 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 34.6 (C¹⁰), 36.3 (C¹¹), 55.5 (—OCH₃), 113.1(C⁶), 114.5 (C³), 114.6 (C¹), 118.6 (C⁸), 120.0 (

), 120.0 (

), 122.5 (

), 127.7 (C^(4a)), 129.7 (

), 129.7 (

), 130.6 (C⁹), 133.9 (C^(5a)), 134.7 (C⁴), 140.0 (C^(9a)), 141.4 (

), 145.9 (C^(11a)), 148.6 (C²), 158.9 (C⁷), 190.9 (C⁵).

EXAMPLE 27 2-(2-Methoxyanilino)-7-methoxydibenzosuberone (10h)

For the preparation of compound 10h by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.25 g (2.0 mmol) of2-methoxyaniline, 0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Yield: 0.55g (85%);

m.p.: 145.0° C.;

C₂₃H₂₁NO₃ (Mr=359.43); GC 49.7 min

MS m/z (%): 359 (100, M⁺), 344 (5, M⁺-CH₃), 326 (2), 316 (3), 208 (3),196 (14), 183 (16), 165 (7), 152 (2), 136 (2), 121 (5), 108 (2).

IR (ATR) 3323 (N—H), 3002 (C—H)_(arom), 1956-2829 (C—H)_(aliph), 1557(C═O), 1520, 1489, 1322, 1289, 1271, 1252, 1211, 1111, 1027, 866, 754.

¹H-NMR (DMSO-d6) δ in ppm: 2.98 (s, 4H, —CH₂—CH₂), 3.76 (s, 3H, —OCH₃),3.79 (s, 3H, —OCH₃), 6.71 (s, 1H, C¹—H), 6.83 (d, 1H, J=8.9 Hz, C³—H),6.97-7.09 (m, 3H,

—H,

—H,

—H), 7.19-7.30 (m, 2H, C⁸—H, C⁹—H), 7.38 (s, 1H, C⁶—H), 7.93 (d, 1H,J=8.8 Hz, C⁴—H), 8.17 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.4 (C¹¹), 55.5 (—OCH₃), 55.8(—OCH₃), 112.4 (C⁶), 112.8 (C³), 114.1 (

), 114.7 (C¹), 118.4 (C⁸), 121.0 (

), 122.7 (

), 124.6 (

), 127.1 (C^(4a)), 129.6 (

), 130.5 (C⁹), 133.7 (C^(5a)), 134.5 (C⁴), 140.2 (C^(9a)), 145.6(C^(11a)), 149.7 (

), 152.3 (C²), 158.0 (C⁷), 190.6 (C⁵).

EXAMPLE 28 2-(3-Methyl-4-fluoroanilino)-7-methoxydibenzosuberone (10i)

For the preparation of compound 10i by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.25 g (2.0 mmol) of 3-methyl,4-fluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Yield: 0.51g (78%);

m.p.: 158.9° C.; C₂₃H₂₀FNO₂ (Mr=361.42); GC 39.8 min

MS m/z (%): 361 (100, M⁺), 346 (6, M⁺-CH₃), 333 (9), 237 (2, M⁺-3-CH₃,4-F-aniline), 208 (10), 178 (3), 165 (10).

IR (ATR) 3363 (N—H), 3013 (C—H)_(arom), 2934-2838 (C—H)_(aliph), 1582,1561 (C═O), 1501, 1286, 1270, 1210, 1048, 971, 862, 806, 768.

¹H-NMR (DMSO-d6) δ in ppm: 2.21 (s, 3H, —CH₃), 3.00 (s, 4H, —CH₂—CH₂),3.77 (s, 3H, —OCH₃), 6.75 (s, 1H, C¹—H), 6.89 (d, 1H, J=8.8 Hz, C³—H),7.00-7.14 (m, 4H, C⁸—H, C⁹—H,

—H,

—H), 7.22 (d, 1H, J=8.3 Hz,

—H), 7.39 (s, 1H, C⁶—H) 7.96 (d, 2H, J=8.8 Hz, C⁴—H), 8.69 (s, 1H,—NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 14.7 (—CH₃), 33.5 (C¹⁰), 36.3 (C¹¹), 55.7(—OCH₃), 112.6 (C⁶), 114.0 (C³), 114.7 (C¹), 115.9 (

), 118.5 (C⁸), 119.9 (

), 123.8 (

), 125.4 (

), 127.4 (C^(4a)), 130.5 (C⁹), 134.0 (C^(5a)), 134.5 (C⁴), 137.3 (

), 140.1 C^(9a)), 145.9 (C^(11a)), 149.2 (C²), 156.8 (

), 158.1 (C⁷), 190.6 (C⁵).

EXAMPLE 29 2-(2-Amino-4-trifluoromethylanilino)-7-methoxydibenzosuberone(10j)

For the preparation of compound 10j by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.4 g (1.9 mmol) of2-nitro-4-trifluoromethylaniline, 0.05 g of Pd(OAc)₂, 0.10 g of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Purificationof the nitro compound is carried out by recrystallization with MeOH.Without further purification, 0.5 g of the nitro compound, 2.9 g ofZnCl₂×2 H₂O in 20 ml EtOH are reduced by method D. M.p.: 78.9° C.;

GC: 50.8 min;

C₂₃H₁₉F₃N₂O₂ (Mr=412.42)

MS m/z (%): 412 (100, M⁺), 397 (8, M⁺-CH₃), 383 (4), 369 (6), 263 (6),237 (M⁺-2-NH₂, 4-CF₃-aniline), 208 (4), 192 (4), 175 (13).

IR (ATR): 3344 (N—H), 2943 (C—H)_(aliph), 1567 (C═O), 1520, 1496, 1333,1283, 1260, 1213, 1162, 1147, 1112, 1036.

¹H-NMR (DMSO-d6) δ in ppm: 3.00 (s, 4H, —CH₂—CH₂—), 3.77 (s, 3H, —OCH₃),5.33 (s, 2H, —NH₂), 6.62 (s, 1H, C¹—H), 6.76 (d, 1H, J=8.8 Hz, C³—H),6.85 (d, 1H, J=8.1 Hz,

—H), 7.01-7.06 (m, 2H,

—H,

—H), 7.25-7.21 (m, 2H, C⁸—H, C⁹—H), 7.39 (s, 1H, C⁶—H), 7.95 (d, 1H,J=8.7 Hz, C⁴—H), 8.09 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.3 (C¹¹), 55.5 (—OCH₃), 111.7(

), 123.2 (

) 113.1 (C⁶), 114.3 (C³), 114.7 (C¹), 118.6 (C⁸), 125.5 (—CF₃), 124.0 (

), 125.8 (

), 127.5 (C^(4a)), 129.3 (

), 130.6 (C⁹), 133.8 (C^(5a)), 134.6 (C⁴), 140.1 (C^(9a)), 143.2 (

), 145.7 (C^(11a)), 149.4 (C²), 158.1 (C⁷), 190.7 (C⁵).

EXAMPLE 30 2-(Phenyl)-7-methoxydibenzosuberone (10k)

A mixture of 0.137 g (0.50 mmol) of 2-chloro-7-methoxydibenzosuberone,0.092 mg (0.75 mmol) of phenylboronic acid, 2.2 mg (2 mol %) of Pd(OAc),0.138 g (1.0 mol) of K₂CO₃, 4.0 g of PEG-400 are stirred at 45° C. for 5h, until a complete reaction is observed on the TLC. 15 ml of NaOH areadded to the mixture and the mixture is extracted 4× with 15 ml ofdiethyl ether each time. Concentration is carried out in vacuo.Purification is carried out via flash chromatography (SiO₂, hexane/ethylacetate 9+1). Yield: 0.05 g (32%); m.p.: 97.8° C.;

C₂₂H₁₈O₂ (Mr=314.39); GC 24.7 min

MS m/z (%): 314 (100, M⁺); 299 (11, M⁺-CH₃), 285 (20), 271 (11), 25512), 239 (11), 228 (6), 215 (5), 178 (4), 165 (10), 120 (4).

IR (ATR) 3027 (C—H)_(arom), 2993-2834 (C—H)_(aliph), 1640, 1601 (C═O),1493, 1287 (C—O), 1245, 1048, 977, 805, 770, 701.

¹H-NMR (DMSO-d6) δ in ppm: 2.47-2.51 (m, 4H, —CH₂—CH₂), 3.78 (s, 3H,—OCH₃), 7.08-7.12 (m, 1H,

—H), 7.26 (d, 1H, J=8.4 Hz, C³—H), 7.40-7.48 (m, 4H, C¹—H, C⁶—H, C⁸—H,C⁹—H), 7.64 (m, 4H,

—H,

—H,

H,

—H), 7.97 (d, 1H, J=8.8 Hz, C²—H).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 35.0 (C¹¹), 55.6 (—OCH₃), 114.2(C⁶), 119.5 (C⁸), 125.0 (C³), 127.3 (

), 127.3 (

), 128.1 (

), 128.7 (C⁹), 129.4 (

), 129.4 (

), 131.4 (C¹), 131.5 (C⁴), 134.9 (C^(4a)), 136.9 (C^(5a)), 139.1(C^(9a)), 139.1 (

), 143.4 (C²), 144.3 (C^(11a)), 158.1 (C⁷), 193.7 (C⁵).

EXAMPLE 31 2-(2,4-Difluoroanilino)-7-methoxydibenzosuberenone (101)

For the preparation of compound 101 by method C, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberenone, 0.25 g (1.9 mmol) of2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol)of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g ofKO-tert-Bu, 5 ml of toluene and 1 ml of tert-BuOH are used. Yield: 0.53g (81%);

m.p.: 202.4° C.; C₂₂H₁₅F₂NO₂ (Mr=363.37); GC 36.2 min

MS m/z (%): 363 (100, M⁺), 335 (52), 292 (48), 272 (6), 152 (13), 13),145 (10), 136 (5).

IR (ATR) 3313 (N—H), 3098-3018 (C—H)_(arom), 2923-2851 (C—H)_(aliph),1611, 1566 (C═O), 1531, 1498, 1360, 1345, 1280, 1259, 1096, 847, 834

¹H-NMR (DMSO-d6) δ in ppm: 3.87 (s, 3H, —OCH₃), 6.86-6.92 (m, 2H, C¹—H,C³—H), 6.99-7.11 (m, 3H,

—H,

—H,

—H), 7.28-7.47 (m, 3H, C⁸—H, C¹⁰—H, C¹¹—H), 7.63-7.72 (m, 2H, C⁶—H,C⁹—H), 8.11 (d, 2H, C⁴—H), 8.65 (s, 1H, —NH).

¹³C-NMR (DMSO-d6) δ in ppm: 55.8 (—OCH₃), 105.4 (dd, J=24.1 Hz,

) 112.2 (d, J=25.7 Hz,

), 113.1 (C⁶), 114.0 (C¹), 115.9 (C³), 119.9 (C⁸), 125.3 (d, J=12.1,

), 126.3 (d, J=9.7 Hz,

), 128.6 (C^(4a)), 128.7 (C^(5a)), 130.0 (C¹⁰), 131.7 (C¹¹), 133.1 (C⁹),134.2 (C⁴), 137.6 (C^(9a)), 139.7 (C^(11a)), 149.1 (C²), 155.0 (d,J=163.7 Hz,

) 160.0 (d, J=163.7 Hz,

), 160.0 (C⁷), 188.1 (C⁵).

EXAMPLE 322-(2,4-Difluoroanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14a)

For the preparation of the compound by method C, 0.67 g (1.8 mmol) of2-chloro-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield:0.57 g(68%); m.p.: 114.6° C.;

C₂₇H₂₅F₂₂O₄ (Mr=465.50); GC 76.6 min

MS m/z (%): 465 (100, M⁺), 450 (6, M⁺-CH₃), 390 (36), 364 (42), 351,(40), 35 (7), 323 (11), 178 (38), 165 (16), 115 (13), 101 (31).

IR (ATR) 3352 (N—H), 2997-2944 (C—H)_(aliph), 1560, 1509 (C═O), 1289,1262, 1140, 843, 814, 802

¹H-NMR (DMSO-d6) δ in ppm: 1.29 (s, 3H, —CH₃), 1.34 (s, 3H, —CH₃), 3.31(s, 4H, —CH₂—CH₂), 3.72-4.45 (m, 5H, —OCH₂—, —CH—, —CH₂O—), 6.60 (s, 1H,C¹—H), 6.73 (d, 1H, J=9.3, C³—H), 7.00-7.47 (m, 6H, C⁶—H, C⁸—H, C⁹—H),

—H,

—H,

—H), 7.94 (d, 1H, J=8.6, C⁴—H), 8.54 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 25.8 (—CH₃), 26.9 (—CH₃), 33.5 (C¹¹), 36.2(C¹⁰), 66.0 (—CH₂—O—), 69.2 (—O—CH₂—), 74.1 (—OCH—), 105.3 (d, J=24.3

), 109.2 (—C—), 112.1 (d, J=21.9 (

), 112.6 (C⁶), 113.9 (C³), 115.4 (C¹); 119.1 (C⁸), 125.3 (d, J=12.0,

), 126.4 (d, J=9.8,

), 127.7 C^(4a)), 130.6 (C⁹), 133.8 (C^(5a)), 134.9 (C⁴) 140.1 (C^(9a)),145.7 (C^(11a)), 149.5 (C²), 154.5 (d, J=152.8,

), 157.2 (C⁷); 160.2 (d, J=169.5,

) 190.7 (C⁵).

EXAMPLE 332-(2,4-Difluoroanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14b)

For the preparation of the compound by method C, 0.67 g (1.8 mmol) of2-chloro-7-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield:65%; C₂₇H₂₅F₂₂O₄ (Mr=465.50)

EXAMPLE 342-(Aminoanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14c)

For the preparation of the compound by method C, 0.67 g (1.8 mmol) of2-chloro-7-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,1.0 (9.2 mmol) g of 1,2-phenylenediamine, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. C₂₇H₂₈N₂O₄(Mr=444.54)

¹H-NMR (DMSO-d6) δ in ppm: 1.29 (s, 3H, —CH₃), 1.34 (s, 3H, —CH₃), 2.96(s, 4H, —CH₂—CH₂—), 3.72-3.79 (m, 1H, —CH₂O—), 4.01-4.31 (m, 3H, —CH₂O—,—CH₂O—), 4.37-4.42 (m, 1H, —CH—), 4.83 (s, 2H, —NH₂), 6.45 (s, 1H,C¹—H), 6.53-6.63 (m, 2H,

—H,

—H), 6.77 (d, 1H, J=7.4,

—H), 6.90-7.05 (m, 3H, C³—H, C⁸—H,

—H), 7.20 (d, 1H, J=8.4, C⁹—H), 7.39 (s, 1H, C⁶—H), 7.91-7.96 (m, 2H,C⁴—H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 25.8 (—CH₃), 26.9 (—CH₃), 33.6 (C¹⁰), 36.6(C¹¹), 66.1 (C³-glyceryl), 69.2 (C¹-glyceryl), 74.1 (C²-glyceryl), 112.1(C⁶), 113.1 (C³), 115.5 (C¹), 115.8 (

), 116.8 (

), 118.8 (C⁸), 125.2 (

); 126.2 (

), 126.2 (

), 126.4 (C^(4a)), 130.4 (C⁹), 133.9 (C^(5a)), 134.8 (C⁴), 140.3(C^(9a)), 144.0 (

), 145.8 (C^(11a)), 151.1 (C²), 157.2 (C⁷), 190.2 (C⁵).

EXAMPLE 352-(2-Aminoanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14d)

For the preparation of the compound by method C, 0.67 g (1.8 mmol) of2-chloro-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,1.0 (9.2 mmol) g of 1,2-phenylenediamine, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield:72%; C₂₇H₂₈N₂O₄ (Mr=444.54)

¹H-NMR (DMSO-d6) δ in ppm: 1.29 (s, 3H, —CH₃), 1.35 (s, 3H, —CH₃), 2.96(s, 4H, —CH₂—CH₂—), 3.76 (q, 1H, J₁=6.5, J₂=8.1, —CH₂O—), 3.99-4.12 (m,3H, —CH₂O—, —OCH₂—), 4.39 (quin, 1H, —CH—), 4.83 (s, 2H, —NH₂), 6.46 (s,1H, C¹—H), 6.53-6.63 (m, 2H,

—H,

—H), 6.77 (d, 1H, J=6.99,

—H), 6.92 (d, 1H, J=7.0,

—H), 7.00-7.06 (m, 2H, C³—H, C⁵—H), 7.20 (d, 1H, J=8.2, C⁹—H), 7.40 (s,1H, C⁶—H), 7.92-7.96 (m, 2H, C⁴—H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 25.8 (—CH₃), 26.9 (—CH₃), 33.6 (C¹⁰), 36.6(C¹¹), 66.1 (C³-glyceryl), 69.2 (C¹-glyceryl), 74.1 (C²-glyceryl), 112.1(C⁶), 113.1 (C³), 115.5 (C¹), 115.8 (

), 116.6 (

), 118.8 (C⁸), 125.2 (

), 126.2 (

), 126.2 (

), 126.4 (C^(4a)), 130.4 (C⁹), 133.9 (C^(5a)), 134.8 (C⁴), 140.3(C^(9a)), 144.0 (

), 145.7 (C^(11a)), 151.1 (C²), 157.2 (C⁷), 190.2 (C⁵).

EXAMPLE 362-(2,4-Difluoroanilino)-7-[2R-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14 e)

10 ml of H₂O and 0.25 g (1.3 mmol) of p-toluenesulfonic acid are addedto a solution of 1.0 g (2.1 mmol) of2-(2,4-difluoroanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one.in 40 ml of MeOH. The solution is heated to 50° C. under an argon inertgas atmosphere. After 6 h, the solution is cooled to room temperatureand concentrated in vacuo. A yellow oil is obtained, which is dissolvedagain in ethyl acetate and 5% strength Na₂HCO₃ solution (50 ml). Theorganic phase is separated off and concentrated i. vac. The diolprecipitates out as a white solid. The solid is dissolved inhexane/ethyl acetate (1:1) and the solution is stirred for 1 h. It isfiltered and the filtrate is concentrated i. vac.

Yield: 0.85 g (95%); m.p.: 130.3° C.; C₂₄H₂₁F₂NO₄ (Mr=425.44)

IR (ATR) 3305 (N—H), 2934 (C—H)_(aliph), 1629, 1607, 1569 (C═O), 1510,1327, 1278, 1218, 1097, 847, 781.

¹H-NMR (DMSO-d6) δ in ppm: 3.32 (s, 4H, —CH₂—CH₂), 3.40-3.46 (m, 2H,—CH₂ OH), 3.77-4.05 (m, 3H, —CHOH—, —OCH₂—), 4.66 (t, 1H, J=5.7,—CH—OH), 4.94 (d, 1H, J=4.9, —CH₂—OH), 6.60 (s, 1H, C¹—H), 6.73 (d, 1H,J=8.9, C³—H), 7.01-7.10 (m, 2 h,

—H,

—H), 7.22 (d, 1H, J=8.3,

—H), 7.30-7.47 (m, 3H, C⁶—H, C⁸—H, C⁹—H), 7.94 (d, 1H, J=8.8, C⁴—H),8.54 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹¹), 36.3 (C¹⁰), 63.1 (—CH₂—OH), 70.2(—O—CH₂—), 70.3 (—OCH—), 105.3 (d, J=24.3,

), 112.1 (d, J=21.9,

), 112.6 (C⁶), 113.8 (C³), 115.4 (C¹), 119.1 (C⁸), 125.3 (d, J=12.0,

), 126.4 (d, J=9.8,

), 127.7 (C^(4a)), 130.6 (C⁹), 133.8 (C^(5a)), 134.6 (C⁴), 139.9(C^(9a)), 145.7 (C^(11a)), 149.4 (C²), 154.5 (d, J=152.8,

), 157.6 (C⁷), 160.2 (d, J=169.5,

), 190.8 (C⁵).

EXAMPLE 372-(2,4-Difluoroanilino)-7-[2S-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14 f)

10 ml of H₂O and 0.25 g (1.3 mmol) of p-toluenesulfonic acid are addedto a solution of 1.0 g (2.1 mmol) of2-(2,4-difluoroanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-onein 40 ml of MeOH. The solution is heated to 50° C. under an argon inertgas atmosphere. After 6 h, the solution is cooled to room temperatureand concentrated in vacuo. A yellow oil is obtained, which is dissolvedagain in ethyl acetate and 5% strength Na₂HCO₃ solution (50 ml). Theorganic phase is separated off and concentrated in vacuo. The diolprecipitates out as a white solid. The solid is dissolved inhexane/ethyl acetate (1:1) and the solution is stirred for 1 h. It isfiltered and the filtrate is concentrated i. vac.

Yield: 95%; C₂₄H₂₁F₂NO₄ (Mr=425.44)

¹H-NMR (DMSO-d6) δ in ppm: 2.99 (s, 4H, —CH₂—CH₂—), 3.41-3.46 (m, 2H,—CH₂O—, —CH—), 3.77-4.03 (m, 3H, —CH₂O—, CH₂ OH), 4.65 (t, 1H, J=5.7,—OH), 4.93 (d, 1H, J=4.8, —OH), 6.60 (s, 1H, C¹—H), 6.73 (d, 1H, J=8.6,C³—H), 7.01-7.41 (m, 6H, C⁶—H, C⁸—H, C⁹—H,

—H,

—H,

—H), 7.94 (d, 1H, J=8.7, C⁴—H), 8.53 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.3 (C¹¹), 63.1 (C³-propoxy),70.2 (C¹-propoxy), 70.3 (C²-propoxy), 105.3 (dd, 1C, J₁=24.2, J₂=26.6,

), 112.2 (dd, 1C, J₁=3.6, J₂=22.0,

), 112.6 (C⁶), 113.8 (C³), 115.4 (C¹), 119.1 (C⁸), 125.1-125.3 (m, 1C,

), 126.4-126.6 (m, 1C,

), 127.8 (C^(4a)), 130.6 (C⁹), 133.8 (C^(5a)), 134.6 (C⁴), 139.9(C^(9a)), 145.7 (C^(11a)), 149.4 (C²), 153.4-156.5 (m, 1C,

), 157.3 (C⁷), 158.3-161.3 (m, 1C,

), 190.8 (C⁵).

EXAMPLE 382-(2-Aminoanilino)-7-[2R-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14g)

10 ml of H₂O and 0.50 g (2.6 mmol) of p-toluenesulfonic acid are addedto a solution of 1.0 g (2.1 mmol) of2-(2-aminoanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-onein 40 ml of MeOH. The solution is heated to 50° C. under an argon inertgas atmosphere. After 6 h, the solution is cooled to room temperatureand concentrated in vacuo. A yellow oil is obtained, which is dissolvedagain in ethyl acetate and 5% strength Na₂HCO₃ solution (50 ml). Theorganic phase is separated off and concentrated i. vac. The diolprecipitates out as a white solid. The solid is dissolved inhexane/ethyl acetate (1:1) and the solution is stirred for 1 h. It isfiltered and the filtrate is concentrated i. vac.

Yield: 96%; C₂₄H₂₄N₂O₄ (Mr=404.47)

¹H-NMR (DMSO-d6) δ in ppm: 2.96 (s, 4H, —CH₂—CH₂—), 3.77-3.82 (m, 2H,—OCH₂—, —CH—), 3.86-4.02 (m, 3H, —OCH₂—, —CH₂O—), 4.65 (t, 1H, J=5.2,—OH), 4.83 (s, 2H, —NH₂), 4.93 (d, 1H, J=4.5, —OH), 6.45 (s, 1H, C¹—H),6.54-6.62 (m, 2H,

—H,

—H), 6.77 (d, 1H, J=7.2,

—H), 6.90-7.03 (m, 3H, C³—H, C⁸—H,

—H), 7.20 (d, 1H, J=8.0, C⁹—H), 7.40 (s, 1H, C⁶—H), 7.91-7.95 (m, 2H,C⁴—H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.6 (C¹¹), 63.1 (C³-propoxy),70.2 (C¹-propoxy), 70.3 (C²-propoxy), 112.1 (C⁶), 113.1 (C³), 115.5(C¹), 115.8 (

), 116.8 (

), 118.9 (C⁸), 125.2 (

), 126.2 (

), 126.3 (

), 126.4 (C^(4a)), 130.4 (C⁹), 134.0 (C^(5a)), 134.5 (C⁴), 140.2(C^(9a)), 144.0 (C²), 145.8 (C^(11a)), 151.1 (C²), 157.6 (C⁷), 190.2(C⁵).

EXAMPLE 392-(2-Aminoanilino)-7-[2S-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14 h)

10 ml of H₂O and 0.50 g (2.6 mmol) of p-toluenesulfonic acid are addedto a solution of 1.0 g (2.1 mmol) of2-(2-aminoanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-onein 40 ml of MeOH. The solution is heated to 50° C. under an argon inertgas atmosphere. After 6 h, the solution is cooled to room temperatureand concentrated in vacuo. A yellow oil is obtained, which is dissolvedagain in ethyl acetate and 5% strength Na₂HCO₃ solution (50 ml). Theorganic phase is separated off and concentrated i. vac. The diolprecipitates out as a white solid. The solid is dissolved inhexane/ethyl acetate (1:1) and the solution is stirred for 1 h. It isfiltered and the filtrate is concentrated i. vac.

Yield: 95%; C₂₄H₂₄N₂O₄ (Mr=404.47)

¹H-NMR (DMSO-d6) δ in ppm: 2.96 (s, 4H, —CH₂—CH₂—), 3.77-3.90 (m, 2H,—CH₂—O—, —CH—), 3.98-4.03 (m, 2H, CH₂ OH, —CH₂O—), 4.66 (s, 1H, —OH),4.83 (s, 2H, —NH₂), 4.93 (s, 1H, —OH), 6.45 (s, 1H, C¹—H), 6.53-6.63 (m,2H,

—H,

—H), 6.77 (d, 1H, J=7.4,

—H), 6.90-7.03 (m, 3H, C⁸—H, C³—H,

—H), 7.20 (d, 1H, J=8.1, C⁹—H), 7.40 (s, 1H, C⁶—H), 7.91-7.95, (m, 2H,C⁴—H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.6 (C¹¹), 65.3 (C³-propoxy),70.2 (C¹-propoxy), 70.3 (C²-propoxy), 112.1 (C⁶), 113.1 (C³), 115.5(C¹), 115.8 (

), 116.8 (

), 118.9 (C⁸), 125.2 (

), 126.2 (

), 126.3 (C¹), 126.4 (C^(4a)), 130.4 (C⁹), 134.0 (C^(5a)), 134.5 (C⁴),140.2 (C⁹a), 144.0 (

), 145.8 (C^(11a)), 151.1 (C²), 157.6 (C⁷), 190.2 (C⁵).

EXAMPLE 402-(2,4-Difluoroanilino)-7-(2-hydroxy-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14i)

For the preparation of the compound by method C, 0.62 g (1.8 mmol) of2-chloro-7-(2-acetoxyethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,-6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield:34%; C₂₃H₁₉F₂NO₃ (Mr=395.41)

¹H-NMR (DMSO-d6) δ in ppm: 2.99 (s, 4H, —CH₂—CH₂—), 3.66-3.74 (m, 2H,—CH₂ —OH), 3.97-4.02 (m, 2H, —OCH₂—), 4.85 (t, 1H, J=5.5, —OH), 6.60 (s,1H, C¹—H), 6.73 (d, 1H, J=8.6, C³—H), 7.01-7.42 (m, 6H, C⁶—H, C⁸—H,C⁹—H,

—H,

—H,

—H), 7.94 (d, 1H, J=8.8, C⁴—H), 8.53 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.2 (C¹¹), 59.9 (C²-ethoxy),70.0 (C′-ethoxy), 105.3 (t, 1C, J=24.2,

), 112-0-112.4 (m, 1C,

), 112.6 (C⁶), 113.8 (C³), 115.4 (C¹), 119.1 (C⁸), 125.1-125.4 (m, 1C,

), 126.3-126.5 (m, 1C,

), 127.7 (C^(4a)), 130.6 (C⁹), 133.8 (C^(5a)), 134.6 (C⁴), 140.0(C^(9a)), 145.7 (C^(11a)), 149.4 (C²), 153.4-156.5 (m, 1C,

), 149.4 (C⁷), 158.3-161.3 (m, 1C,

), 190.8 (C⁵).

EXAMPLE 412-(2,4-Difluoroanilino)-7-(3-hydroxy-propoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14j)

For the preparation of the compound by method C, 0.65 g (1.8 mmol) of2-chloro-7-(3-acetoxypropoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield:40%; C₂₄H₂₁F₂NO₃ (Mr=409.44)

¹H-NMR (DMSO-d6) δ in ppm: 1.85 (quin, 2H, J=6.3, —CH₂—), 2.99 (s, 4H,—CH₂—CH₂—), 3.55 (q, 2H, J=6.1, —CH₂ —OH), 4.04 (t, 2H, J=6.4-OCH₂—),4.54 (t, 1H, J=5.1, —OH), 6.60 (s, 1H, C¹—H), 6.73 (d, 1H, J=8.6, C³—H),7.00-7.42 (m, 6H, C⁶—H, C⁸—H, C⁹—H,

—H,

—H,

—H), 7.94 (d, 1H, J=8.8, C⁴—H), 8.54 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 32.5 (C²-propoxy), 33.6 (C¹⁰), 36.2 (C¹¹),57.6 (C³-propoxy), 65.1 (C¹-propoxy), 105.3 (t, 1C, J=24.2,

), 11.9-112.4 (m, 1C,

), 112.6 (C⁶), 113.8 (C³), 115.3 (C¹), 119.1 (C⁸), 125.1-125.4 (m, 1C,

), 126.3-126.6 (m, 1C,

), 127.8 (C^(4a)), 130.6 (C⁹), 133.8 (C^(5a)), 134.5 (C⁴), 140.0(C^(9a)), 145.7 (C^(11a)), 149.4 (C²), 153.4-156.5 (m, 1C,

), 157.5 (C⁷), 158.3-161.3 (m, 1C,

), 190.8 (C⁵).

EXAMPLE 422-(2,4-Difluoroanilino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(141)

For the preparation of the compound by method C, 0.67 g (1.8 mmol) of2-chloro-7-(2-morpholin-4-yl-ethoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield:76%; C₂₄H₂₁F₂NO₄ (Mr=425.44)

¹H-NMR (DMSO-d6) δ in ppm: 2.42-2.50 (m, 4H, —CH₂—N—CH₂—), 2.67 (t, 2H,—CH₂N—), 2.99 (s, 4H, —CH₂—CH₂—), 3.56 (t, 4H, J=4.6, —CH₂—O—CH₂—), 4.09(t, 2H, J=5.7, —CH₂O—), 6.61 (s, 1H, C⁶—H), 6.73 (d, 1H, J=8.9, C³—H),7.01-7.43 (m, 6H, C¹—H, C⁸—H, C⁹—H,

—H,

—H,

—H), 7.94 (d, 1H, J=8.8, C⁴—H); 8.52 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.5 (C¹⁰), 36.2, 54.0 (2C,C²/C⁶-morpholinyl), 57.3 (C²-ethoxy), 65.9 (C¹-ethoxy), 66.5 (2C,C³/C⁵-morpholinyl), 105.3 (dd, 1C, J₁=24.1, J₂=26.7, C³), 111.9-112.4(m, 1C,

), 112.6 (C⁶), 113.9 (C³), 115.5 (C¹), 119.1 (C⁸), 125.2-125.4 (m, 1C,

), 126.3-126.5 (m, 1C,

), 127.8 (C^(4a)), 130.6 (C⁹), 133.8 (C^(5a)), 134.6 (C⁴), 140.0(C^(9a)), 145.7 (C^(11a)), 149.4 (C²), 154.9 (dd, 1C, J₁=12.6, J₂=142.3,

), 157.3 (C⁷), 159.8 (dd, 1C, J₁=11.5, J₂=138.1,

), 190.8 (C⁵).

EXAMPLE 432-(2-Aminoanilino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14m)

For the preparation of the compound by method C, 0.67 g (1.8 mmol) of2-chloro-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,1.0 (9.2 mmol) g of 1,2-phenylenediamine, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield:74%; C₂₇H₂₉N₃O₃ (Mr=443.55))

¹H-NMR (DMSO-d6) δ in ppm: 2.30-2.50 (m, 4H, —CH₂—N—CH₂—), 2.67 (t, 2H,J=5.5, —CH₂—N—), 2.96 (s, 4H, —CH₂—CH₂—), 3.56 (t, 4H, J=4.3,—CH₂—O—CH₂—), 4.09 (t, 2H, J=5.4, —CH₂O—), 4.83 (s, 2H, —NH₂), 6.45 (s,1H, C¹—H), 6.54-6.63 (m, 2H,

—H,

—H), 6.77 (d, 1H, J=7.6,

—H), 6.92 (d, 1H, J=7.6,

—H), 6.99-7.03 (m, 2H, C³—H, C⁸—H), 7.19 (d, 1H, J=8.3, C⁹—H), 7.38 (s,1H, C⁶—H), 7.91-7.95 (m, 2H, C⁴—H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.6 (C¹⁰), 36.6 (C¹¹), 54.0 (2C,C²/C⁶-morpholinyl), 57.3 (C²-ethoxy), 65.9 (C¹-ethoxy), 66.5 (2C,C³/C⁵-morpholinyl), 112.2 (C⁶), 113.1 (C³), 115.6 (C¹), 115.8 (

), 116.8 (

), 118.8 (C⁸), 125.2 (

), 126.1 (

), 126.2 (

), 126.4 (C^(4a)), 130.4 (C⁹), 133.9 (C^(5a)), 134.6 (C⁴), 140.3(C^(9a)), 144.0 (

), 145.7 (C^(11a)), 151.1 (C²), 157.2 (C⁷), 190.2 (C⁵).

EXAMPLE 442-(2,4-Difluoroanilino)-7-(2-tetrahydropyran-4-yl-oxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14k)

For the preparation of the compound by method C, 0.62 g (1.8 mmol) of2-chloro-7-(2-tetrahydropyran-4-yl-oxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield:56%; C₂₆H₂₃F₂NO₃ (Mr=435.47)

¹H-NMR (DMSO-d6) δ in ppm: 1.52-1.61 (m, 2H, C³/C⁵-tetrahydropyranyl),1.92-1.98 (m, 2H, C³/C⁵-tetrahydropyranyl), 1.99 (s, 4H, —CH₂—CH₂),3.41-3.53 (m, 2H, C²/C⁶-tetrahydropyranyl), 3.78-3.88 (m, 2H,C²/C⁶-tetrahydropyranyl), 4.51-4.67 (m, 1H, C⁴-tetrahydropyranyl), 6.60(s, 1H, C⁶—H), 6.73 (d, 1H, J=8.8, C³—H), 7.04-7.41 (C¹—H, C⁸—H, C⁹—H,

—H,

—H,

—H), 7.94 (d, 1H, C⁴—H), 8.53 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 32.1 (2C, C³/C⁶-tetrahydropyranyl), 33.5(C¹⁰), 36.2 (C¹¹), 64.8 (2C, C²/C⁶-tetrahydropyranyl), 171.9(C⁴-tetrahydropyran), 105.3 (dd, 1C, J₁=24.2, J₂=26.7,

), 112.2 (dd, 1C, J₁=3.7, J₂=22.1,

), 112.6 (C⁶), 113.9 (C³), 117.1 (C¹), 120.4 (C⁸), 125.2-125.4 (m, 1C,

), 126.4 (dd, 1C, J₁=3.2, J₂=9.7,

), 127.7 (C^(4a)), 130.6 (C⁹), 133.8 (C^(5a)), 134.7 (C⁴), 140.2(C^(9a), 145.7 (C^(11a)), 149.5 (C²), 154.9 (dd, 1C, J₁=11.8, J₂=143.5,

), 158.7 (C⁷), 159.8 (dd, 1C, J₁=11.9, J₂=137.6,

), 190.8 (C⁵).

B. Substitution at Position 8 or 9 Method H Bromination of theMethoxymethylbenzoic Acid

The methoxymethylbenzoic acid and NBS are introduced into chlorobenzeneand the reaction mixture is heated to 70° C.

Variant 1

After dropwise addition of AIBN/chlorobenzene, the mixture is stirred at100° C. for a further 2 h 45 min. The solution is then cooled and thechlorobenzene is removed. The product is used further without furtherpurification. The succinimide is removed in the following stage.

Variant 2

After dropwise addition of AIBN/chlorobenzene, the mixture is stirred at70-75° C. for a further 1 h 30 min. The solution is then cooled and thechlorobenzene is removed. The product is used further without furtherpurification. The succinimide is removed in the following stage.

Method I

Wittig reaction of the bromomethylmethoxybenzoic acid with3-chlorobenzaldehyde Triphenylphosphine is introduced into 150 ml ofMeOH, the bromomethylmethoxybenzoic acid (dissolved in MeOH) is addeddropwise, while stirring, and the mixture is heated under reflux for 2hours. NaOMe solution (30% in MeOH) is then slowly added dropwise. Whenthe dropwise addition has ended, after waiting for a further 15 minutes3-chlorobenzaldehyde is then added. Refluxing for 6 h follows.Thereafter, the reaction mixture is poured on to a stirred mixture of 75g of ice and 175 ml of water. In the next step, the mixture is washed 3×with 200 ml of methylene chloride each time. The aqueous phase is thenrendered strongly acid with conc. HCl, while cooling with ice.Thereafter, an oily to semi-solid precipitate forms, which can beseparated off in a separating funnel. The remainder of the product isextracted with methylene chloride.

Method J

Reduction of the chlorophenylvinylmethoxybenzoic acid

Variant 1

The chlorophenylvinylmethoxybenzoic acid is dissolved in methanol, andhydrochloric acid is added. Pd/BaSO₄ (5%) is then added. Afterevacuation, the mixture is flushed with 4 l of H₂. The solution isstirred at room temperature under an H₂ atmosphere for 2 days. Thecharcoal is then filtered off and the mixture is concentrated in vacuo.The oil formed is transferred into a separating funnel with methylenechloride and the organic phase is washed with water. Afterconcentration, a pale yellow oil is obtained, which crystallizes whenleft to stand.

Variant 2

The chlorophenylvinylmethoxybenzoic acid is dissolved in the statedsolvent mixture. Pd/C (10%) is then added. After evacuation, the mixtureis flushed with 4 liters of H₂. The solution is stirred at roomtemperature under an H₂ atmosphere (further H₂ flask) for 4 hours. Thecharcoal is then filtered off and the mixture is concentrated in vacuo.

Method K Cyclization by Means of Friedel-Crafts Acylation

The chlorophenylethylmethoxybenzoic acid is suspended in methylenechloride (dry) and the mixture is flushed with argon. The mixture isthen heated to the reflux temperature and thionyl chloride in methylenechloride is added dropwise to the solution in the course of one hour,while stirring. The mixture is then stirred again for a further hour.The reaction mixture is cooled to room temperature and anhydrous AlCl₃is added in the course of 30 min. Thereafter, the reaction mixture isstirred again for a further 45 min and then poured on to a mixture of 90g of ice and 150 ml of water, while stirring. The hydrolysis mixture isstirred for approx. 30 min. The two phases are then separated. Theorganic phase is concentrated in vacuo.

Method L Methoxy Cleavage on the Ring System

The methoxydihydrodibenzosuberenone is dissolved in glacial acetic acid,and HBr (48%, aqueous) is added. The mixture is heated at 120-130° C.for 3 h.

Variant 1

After hydrolysis with approx. 150 g of ice, the precipitate is filteredoff.

Variant 2

After hydrolysis with approx. 150 g of ice, the precipitate is filteredoff and, after washing with water, the residue on the filter isdissolved again in methylene chloride. The solution is thenconcentrated.

Method M Formation of the Acetal

First toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethylester and then K₂CO₃ are added to a solution of thedihydrodibenzosuberenone in DMF. The reaction mixture is heated to 80°C. under argon and cooled again to room temperature after 24 h. Themixture is then taken up in 50 ml of water and extracted with ethylacetate and the combined organic phases are washed with NaOH and driedover Na₂SO₄. The mixture is then concentrated i. vac., a brown oil beingobtained, which is purified via flash (SiO₂, hexane/ethyl acetate. Thepure acetal is obtained.

Method N Cleavage of the Acetal

H₂O and p-toluenesulfonic acid are added to a solution of the acetal inMeOH. The solution is heated to 50° C. under an inert gas. After 6 h,the solution is cooled to room temperature and concentrated i. vac. Ayellow oil is obtained, which is dissolved again in ethyl acetate and 5%strength Na₂HCO₃ solution (50 ml). The organic phase is separated offand concentrated i. vac.

Method O Introduction of Radicals Via the Buchwald—Hartwig Reaction

A mixture of chlorodihydrodibenzosuberenone, Pd(OAc)₂, phosphine ligand(2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl), NaOtert-Bu,amino substituent, toluene, tert-BuOH is stirred at 100° C. for 3-5 h.Thereafter, the mixture is cooled, taken up in 150 ml of water andextracted with diethyl ether. The combined org. phases are concentratedi. vac. and the residue is purified by column chromatography (flash;SiO₂; hexane/ethyl acetate).

Method P

Substitution with Alcohols

A solution of chlorohydroxydibenzodihydrodibenzosuberenone, alcohol,triphenylphosphine and THF is prepared under an inert gas. Afterdropwise addition of the carboxylate, the mixture is stirred at 0° C.for 1 h. The reaction is continued to the end at room temperature.Thereafter, the mixture is concentrated i. vac.

Method Q

Substitution with Alkyl Halides

A mixture of phenol, alkyl halide and K₂CO₃ is heated to 80° C. in thestated solvent, stirred for 3 h, cooled to RT and dissolved again in EAand water. The org. phase is washed with water and alkali, dried overNa₂SO₄ and concentrated i. vacuo.

Method R Preparation of the Triflate

Tf₂O is slowly added to a stirred solution of the phenol in pyridine at0° C. (ice-bath) under argon over a period of 0.5 h. The reactionmixture is stirred overnight at room temperature and extracted with EAand the organic phase is washed with 10% strength HCl and 5% strengthNaHCO₃ solution, dried over Na₂SO₄, filtered and concentrated.

Substitution in Position 8—Compounds and Precursors EXAMPLE 454-Methoxy-2-methylbenzoic acid (6)

For the synthesis of the title compound, 6.64 g (0.040 mol) of4-methoxy-2-methylbenzoic acid, 7.1 g (0.040 mol) of NBS and 0.25 g ofAIBN in 150 ml of chlorobenzene are reacted by method H (variant 2).C₉H₁₀O₃ (Mr=166.18)

EXAMPLE 46 2-[2-(3-Chlorophenyl)-vinyl]-4-methoxybenzoic acid (7)

For the synthesis of the title compound, 45.6 g (0.186 mol) of2-bromomethyl-4-methoxybenzoic acid, 48.8 g (0.186 mol) oftriphenylphosphine, 26.1 g (0.186 mol) of 3-chlorobenzaldehyde and 84.0g (0.435 mol) of NaOMe (28%) in 150 ml of methanol are reacted by methodI. Purification is carried out by recrystallization from methanol at 4°C.

C₁₆H₁₃ClO₃ (Mr=288.73)

¹H-NMR (DMSO-d6) δ in ppm: 3.86 (s, 3H, —OCH₃), 6.96 (d, 1H, J=8.78 Hz,C⁵—H), 7.12-7.59 (m, 6H, C³—H and C^(4′)—/C^(5′)—/C^(6′)—H and C¹—/C²—Hvinyl), 7.89 (d, 1H, J=8.72 Hz, C^(2′)), 8.01-8.09 (m, 1H, C⁶).

¹³C-NMR (DMSO-d6) δ in ppm: 55.9 (—OCH₃), 112.1 (C³), 113.9 (C⁵), 122.0(C¹), 125.5 (C^(6′)), 126.7 (C^(2′)), 127.9 (C^(4′)), 129.6 (C¹ vinyl),129.6 (C² vinyl), 131.0 (C^(5′)), 133.3 (C⁶), 133.9 (C^(3′)), 139.9(C^(1′)), 140.7 (C¹), 162.3 (C⁴), 168.2 (—COOH).

EXAMPLE 47 2-[2-(3-Chlorophenyl)-ethyl]-4-methoxybenzoic acid (8)

For the synthesis of the title compound, 6.0 g of2-[2-(3-chlorophenyl)-vinyl]-4-methoxybenzoic acid, 0.6 g of Pd/C (10%)and 41 of hydrogen are employed in method J (variant 2). The solventmixture comprises 75 ml of acetonitrile, 75 ml of ethyl acetate and 20ml of methanol. C₁₆H₁₅ClO₃(Mr=290.75)

EXAMPLE 48 2-Chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(9)

For the synthesis of the title compound, 16.6 g (0.057 mol) of[2-(3-chlorophenyl-ethyl]-4-methoxybenzoic acid, 7.25 g (0.06 mol) ofSOCl₂, 250 ml of methylene chloride and 10 g of AlCl₃ (0.075 mol) areemployed in method K. Purification is carried out by columnchromatography (flash; SiO₂; hexane 90%/ethyl acetate 10%).C₁₆H₁₃ClO₂(Mr=272.73)

MS m/z (%): 274/272 (34/100, M⁺), 259/257 (2/5, M⁺-CH₃), 246/244 (9/26,M⁺-CO), 237 (19, M⁺-Cl), 231/229 (5/17, 259/257-CO), 208 (17, 244-Cl),194 (10, 231/229-Cl), 178 (14, 194-O), 165 (43,4-methoxy-2-methylbenzoic acid).

IR (ATR) 2921, 2852, 1595, 1266, 1203, 1185, 1110, 1031, 942, 912, 874,839, 814, 769, 722, 596, 537 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 3.11 (s, 4H, —CH₂—CH₂—), 3.82 (s, 3H, —OCH₃),6.87-6.96 (m, 2H, C⁷—/C⁹—H), 7.37-7.46 (m, 2H, C¹—/C³—H), 7.87 (d, 1H,J=8.37 Hz, C⁶—H), 7.99 (d, 1H, 8.70 J=8.70 Hz, C⁴—H).

¹³C-NMR (DMSO-d6) δ in ppm: 34.0 (C¹¹), 35.1 (C¹⁰), 55.8 (—OCH₃), 113.1(C⁷), 114.6 (C⁹), 126.9 (C³), 129.0 (C¹), 130.0 (C^(5a)), 132.7 (C⁶),133.7 (C⁴), 137.1 (C^(4a)), 137.5 (C²), 144.5 (C^(9a)), 145.7 (C^(11a)),163.1 (C⁸), 191, (C⁵).

EXAMPLE 49 2-Chloro-8-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(10)

For the synthesis of the title compound, 1.0 g (4.87 mmol) of2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 10 ml ofHBr (48%, aqueous) and 10 ml of glacial acetic acid are employed inmethod L. C₁₅H₁₁ClO₂(Mr=258.71)

EXAMPLE 50(S)-2-Chloro-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(14)

For the preparation of the title compound, 0.50 g (1.9 mmol) of2-chloro-8-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.75 g(2.6 mmol) of (R)-toluene-4-sulfonic acid2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester and 0.80 g (5.8 mmol) ofK₂CO₃ in 10 ml of dry DMF are reacted by method M. C₂₁H₂₁ClO₄(Mr=372.85)

EXAMPLE 51(S)-2-(2,4-Difluorophenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(12a)

For the synthesis of the title compound, 0.81 g (0.0022 mol) of(S)-2-chloro-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one,0.25 g (0.0019 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)₂,0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10ml of toluene and 2 ml of tert-BuOH are reacted by method O.Purification is carried out by column chromatography (flash; SiO₂;hexane 80%/ethyl acetate 20%).

C₂₇H₂₅F₂NO₄ (Mr=465.50)

EXAMPLE 52(R)-2-(2,4-Difluorophenylamino)-8-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(12c)

For the synthesis of the title compound, 0.10 g (0.215 mmol) of(S)-8-(2,4-difluorophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-oneand 0.0054 g (0.0284 mmol) of p-toluenesulfonic acid monohydrate in 6 mlof methanol and 1.5 ml of water are reacted by method N. C₂₄H₂₁F₂NO₄(Mr=425.44)

¹H-NMR (DMSO-d6) δ in ppm: 2.95-3.09 (m, 4H, —CH₂—CH₂—), 3.42-3.45 (m,2H, dihydroxypropoxy), 3.76-3.81 (m, 1H, dihydroxypropoxy), 3.89-3.97(m, 1H, dihydroxypropoxy), 4.04-4.11 (m, 1H, dihydroxypropoxy), 4.86 (s,2H, C²—/C³—OH dihydroxypropoxy), 6.61 (s, 1H, C¹—H), 6.72 (d, 1H, J=9.55Hz, C³—H), 6.85-6.87 (m, 2H, C^(3′)—/C^(6′)-H), 7.05-7.12 (m, 1H,C^(5′)-H), 7.30-7.47 (m, 2H, C⁷—/C⁹—H), 7.95 (d, 2H, J=8.59 Hz,C⁶—/C⁴—H), 8.49 (s, 1H, —NH₂).

EXAMPLE 53(S)-2-(2-Aminophenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(12b)

For the synthesis of the title compound, 0.91 g (0.0024 mol) of(S)-2-chloro-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one,1.00 g (0.0092 mol) of phenylenediamine, 2 spatula tips of Pd(OAc)₂,0.18 g of phosphine ligand and 1.60 g (0.0166 mol) of NaOtert-Bu in 10ml of toluene and 2 ml of tert-BuOH are reacted by method O.

Purification is carried out by column chromatography (flash; SiO₂;hexane 70%/ethyl acetate 30%). C₂₇H₂₈N₂O₄ (Mr=444.54)

¹H-NMR (DMSO-d6) δ in ppm: 1.30 (s, 3H, —CH₃), 1.35 (s, 3H, —CH₃),2.92-3.05 (m, 4H, —CH₂—CH₂—), 3.71-3.78 (m, 1H, dioxolane), 3.99-4.13(m, 3H, dioxolane), 4.38-4.44 (m, 1H, dioxolane), 4.83 (s, 2H, —NH₂),6.46-7.03 (m, 9H, C¹—/C³—/C⁴—/C⁷—/C⁹—H andC^(3′)—/C^(4′)—/C^(5′)—/C^(6′)—H), 7.91 (s, 1H, C⁶—H), 7.96 (s, 1H,—NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 25.7 (—CH₃), 27.0 (—CH₃), 35.1 (C¹¹), 36.1(C¹⁰), 66.0 (C³ dioxolane), 69.2 (C¹ dioxolane), 73.9 (C² dioxolane),109.3 (—C—(CH₃)₂—), 112.0 (C⁷), 112.9 (C⁹), 113.0 (C³), 114.3 (C¹),115.8 (C^(3′)), 116.8 (C^(4′)), 125.3 (C^(4a)), 126.1 (C^(5′)), 126.3(C^(6′)), 126.7 (C^(5a)) 131.8 (C^(1′)), 133.6 (C⁶), 133.9 (C⁴), 144.0(C^(2′)), 145.0 (C^(9a)), 145.4 (C²), 150.8 (C^(11a)), 161.3 (C⁸), 188.7(C⁵).

EXAMPLE 54(R)-2-(2-Aminophenylamino)-8-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(12d)

For the synthesis of the title compound, 0.10 g (0.225 mmol) of(S)-2-(2-amino-phenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-oneand 0.0537 g (0.282 mmol) of p-toluenesulfonic acid monohydrate in 6 mlof methanol and 1.5 ml of water are reacted by method N. C₂₄H₂₄N₂O₄(Mr=404.47)

¹H-NMR (DMSO-d6) δ in ppm: 2.83-3.00 (m, 4H, —CH₂—CH₂—), 3.43 (d, 2H,J=4.80 Hz, C³—H dihydroxypropoxy), 3.93-4.05 (m, 3H, dihydroxypropoxy),4.68 (s, 1H, C³—OH), 4.83 (s, 2H, —NH₂), 4.96 (s, 1H, C³—OH), 6.44 (s,1H, C^(6′)), 6.54-7.03 (m, 8H, C¹—/C³—/C⁴—/C⁷—/C⁹—H andC^(3′)—/C^(4′)—/C^(5′)—H), 7.89-7.96 (m, 2H, C⁶—H, —NH—)

¹³C-NMR (DMSO-d6) δ in ppm: 35.2 (C¹¹), 36.1 (C¹⁰), 63.0 (C³dihydroxypropoxy), 70.1 (C¹ dihydroxypropoxy), 70.2 (C²dihydroxypropoxy), 112.0 (C⁹), 112.8 (C⁷), 113.0 (C³), 114.3 (C¹), 115.8(C^(3′)), 116.8 (C^(4′)), 125.4 (C^(4a)), 126.1 (C^(6′)), 126.3(C^(5′)), 126.7 (C^(5a)), 131.5 (C^(1′)), 133.9 (C⁴), 144.0 (C^(2′)),145.0 (C^(9a)), 145.4 (C²), 150.8 (C^(11a)), 161.8 (C⁸), 188.7 (C⁵)

EXAMPLE 552-Chloro-8-(2-morpholin-4-ylethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(17)

For the synthesis of the title compound, 0.44 g (1.69 mmol) of2-chloro-8-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.345 g(1.86 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.93 g(6.75 mmol) of K₂CO₃ in 15 ml of acetonitrile are reacted by method Q.C₂₁H₂₂ClNO₃(Mr=371.87)

¹H-NMR (DMSO-d6) δ in ppm: 2.47 (under DMSO, 4H, C²—/C⁶—H morpholine),2.68 (t, 2H, J=5.73 Hz, C²—H ethylmorphine), 3.10 (s, 4H, —CH₂—CH₂—cyclohexane), 3.53-3.58 (m, 4H, C³—/C⁵—H morpholine), 4.15 (t, 2H,J=5.69 Hz, C¹—H ethylmorpholine), 6.88-6.96 (m, 2H, C⁷—/C⁹—H), 7.36-7.44(m, 2H, C¹—/C³—H), 7.87 (d, 1H, J=8.37 Hz, C⁶—H), 7.98 (d, 1H, J=8.64Hz, C⁴—H).

¹³C-NMR (DMSO-d6) δ in ppm: 34.0 (C¹¹), 35.1 (C¹⁰), 54.0 (2C,C²/C⁶-morpholine), 57.2 (C² ethylmorpholine), 66.0 (C¹ ethylmorpholine),66.5 (2C, C³/C⁵ morpholine), 113.5 (C⁷), 115.2 (C⁹), 126.9 (C³), 129.0(C¹), 130.0 (C^(5a)), 132.7 (C⁶), 133.7 (C⁴), 137.1 (C^(4a)), 137.5(C²), 144.5 (C^(9a)), 145.7 (C^(11a)), 162.3 (C⁸), 191.0 (C⁵).

EXAMPLE 562-(2,4-Difluorophenylamino)-8-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(12e)

For the synthesis of the title compound, 0.45 g (0.0013 mol) of8-chloro-1-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one,0.20 g (0.0015 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)₂,0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10ml of toluene and 2 ml of tert-BuOH are reacted by method O.

Purification is carried out by column chromatography (flash; SiO₂;hexane 80%/ethyl acetate 20%).

C₂₇H₂₆F₂N₂O₂ (Mr=464.52)

¹H-NMR (DMSO-d6) δ in ppm: 2.49 (under DMSO, 4H, C²—/C⁶—H morpholine),2.69 (t, 2H, J=5.51 Hz, C²—H ethylmorpholine), 2.96-3.07 (m, 4H,—CH₂—CH₂— cycloheptane), 3.56 (t, 4H, J=4.50 Hz, C³—/C⁵—H morpholine),4.15 (t, 2H, J=5.44 Hz, C¹—H ethylmorpholine), 6.61 (s, 1H, C¹—H), 6.73(d, 1H, J=8.43 Hz, C³—H), 6.86-6.91 (m, 2H, C^(3′)—/C^(6′)—H), 7.05-7.13(m, 1H, C^(5′)—H), 7.30-7.47 (m, 2H, C⁷—/C⁹—H), 7.95 (d, 2H, J=8.66 Hz,C⁴—/C⁶—H), 8.49 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 35.1 (s, C¹¹), 35.8 (s, C¹⁰), 53.9 (s, 2C,C²/C⁶ morpholine), 57.3 (s, C² ethylmorpholine), 65.9 (s, C¹,ethylmorpholine), 66.5 (s, 2C, C³/C⁵ morpholine), 105.3 (dd, J₁=25.5 Hz,J₂=24.2 Hz, C^(3′)), 112.2 (dd, J₁=21.9 Hz, J₂=3.8 Hz, C^(5′)), 112.5(s, C⁷), 113.1 (s, C⁹), 113.6 (s, C⁹), 114.5 (s, C¹), 125.5 (dd, J₁=12.0Hz, J₂=3.4 Hz, C^(1′)), 126.3 (dd, J₁=9.5 Hz, J₂=3.1 Hz, C^(6′)), 128.2(s, C^(4a)), 131.3 (s, C^(5a)), 133.6 (s, C⁶), 133.8 (s, C⁴), 145.1 (s,C²), 145.3 (s, C^(11a)), 149.1 (s, C^(9a)), 154.9 (dd, J₁=141.3 Hz,J₂=11.0, C^(4′)), 159.7 (dd, J₁=129.7 Hz, J₂=12.0 Hz, C^(2′)), 161.6 (s,C⁸), 189.1 (s, C⁵).

Substitution in Position 9—Compounds and Precursors EXAMPLE 572-Bromomethyl-3-methoxybenzoic acid (1)

for the synthesis of the title compound, 6.64 g (0.040 mol) of3-methoxy-2-methylbenzoic acid, 7.1 g (0.040 mol) of NBS and 0.25 g ofAIBN in 150 ml of chlorobenzene are reacted by method H (variant 1).

C₉H₉BrO₃ (Mr=245.07); yield: 55%

¹H-NMR (DMSO-d6) δ in ppm: 3.89 (s, 3H, —OCH₃), 5.03 (s, 2H, —CH₂—Br),7.23-7.28 (m, 1H, C⁵—H), 7.41-7.46 (m, 2H, C⁴—/C⁵—H), 13.25 (s, 1H,—COOH).

¹³C-NMR (DMSO-d6) δ in ppm: 56.1 (—OCH₃), 68.4 (—CH₂Br), 116.3 (C⁴),116.8 (C⁶), 126.9 (C²), 131.4 (C⁵), 135.3 (C¹), 154.3 (C³), 170.9(—COOH).

EXAMPLE 58 2-[2-(3-Chlorophenyl)-vinyl]-3-methoxybenzoic acid (2)

For the synthesis of the title compound, 45.6 g (0.186 mol) of2-bromomethyl-3-methoxybenzoic acid, 48.8 g (0.186 mol) oftriphenylphosphine, 26.1 g (0.186 mol) of 3-chlorobenzaldehyde and 84.0g (0.435 mol) of NaOMe (28%) in 150 ml of methanol are reacted by methodI. Purification is carried out by recrystallization from methanol withwater.

C₁₆H₁₃ClO₃ (Mr=288.3); yield 51%; m.p.: 119° C.

IR (ATR) 2923, 2360, 2342, 1685, 1587, 1451, 1300, 1275, 1260, 1220,1197, 1178, 1049, 973, 964, 914, 889, 872, 810, 783, 761, 749, 729, 705,684, 667, 621, 530, 457, 432 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 3.86 (s, 3H, —OCH₃), 7.04-7.55 (m, 9H,diphenylethene), 13.03 (s, 1H, —COOH).

¹³C-NMR (DMSO-d6) δ in ppm: 56.3 (O—CH₃), 114.2 (C⁴), 121.4 (C⁶), 124.8(C²), 125.2 (C¹/C² vinyl), 126.2 (C^(6′)), 127.6 (C^(2′)), 128.8(C^(4′)), 130.9 (C⁵), 132.0 (C^(5′)), 133.9 (C¹), 134.0 (C^(3′)), 140.4(C^(1′)), 157.9 (C³), 169.9 (—COOH).

EXAMPLE 59 2-[2-(3-Chlorophenyl)-ethyl]-3-methoxybenzoic acid (3)

For the synthesis of the title compound, 6.0 g of2-[2-(3-chlorophenyl)-vinyl]-3-methoxybenzoic acid, 0.6 g of Pd/BaSO₄(5%), 4 l of hydrogen and 150 ml of methanol are employed in method J(variant 1). Yield: 87%; m.p.: 91° C.; C₁₆H₁₅ClO₃ (Mr=290.75)

IR (ATR) 2947, 2359, 2342, 1691, 1461, 1436, 1276, 1250, 1214, 1089,1058, 1000, 782, 753, 696, 681 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 2.74 (t, 2H, J=8.07 Hz, C¹ ethyl), 3.11 (t,2H, J=8.08, C² ethyl), 3.79 (s, 3H, —OCH₃), 7.15 (d, 2H, C⁴—H andC^(6′)—H), 7.22-7.25 (m, 2H, C⁵—H and C^(5′)—H), 7.27 (s, 1H, C^(2′)—H),7.30-7.37 (m, 2H, C⁶—H and C^(4′)—H).

¹³C-NMR (DMSO-d6) δ in ppm: 28.7 (C¹ ethyl), 35.7 (C² ethyl), 56.3(—OCH₃), 114.2 (C⁴), 122.0 (C⁶), 126.1 (C^(6′)), 127.2 (C^(4′)), 128.3(C^(2′)), 130.3 (C^(5′)), 130.4 (C¹), 132.6 (C²), 133.2 (C^(3′)), 145.0(C^(1′)), 157.8 (C³), 169.4 (—COOH).

EXAMPLE 60 8-Chloro-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(4)

For the synthesis of the title compound, 16.6 g (0.057 mol) of[2-(3-chlorophenyl)-ethyl]-3-methoxybenzoic acid, 7.25 g (0.06 mol) ofSOCl₂, 250 ml of methylene chloride and 10 g of AlCl₃ are employed inmethod K. Purification is carried out by column chromatography (flash;SiO₂; hexane 90%/ethyl acetate 10%).

C₁₆H₁₃ClO₂(Mr=272.73); yield: 47%; m.p.: 75° C.; GC 13.5 min

MS m/z (%): 274/272 (35/100, M⁺), 259/257 (6/18, M⁺-CH₃), 245/243 (5/15,M⁺-CO), 231/229 (3/11, 259/257-CO), 208 (17, 243-Cl), 194 (20,231/229-Cl), 178 (23, 194-O), 165 (44, 3-methoxy-2-methylbenzoic acid).

IR (ATR) 2946, 2901, 2359, 1659, 1589, 1575, 1312, 1284, 1254, 1228,1184, 1087, 1062, 960, 862, 795, 754, 722, 706 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 3.08 (s, 4H, —CH₂—CH₂—) 3.82 (s, 3H, —OCH₃),7.18-7.42 (m, 5H, C²—/C³—/C⁴—/C⁷—/C⁹—H), 7.68 (d, 1H, J=8.28 Hz, C⁶—H).

¹³C-NMR (DMSO-d6) δ in ppm: 26.2 (C¹¹), 32.9 (C¹⁰), 56.4 (—OCH₃), 114.9(C²), 121.7 (C⁴), 127.0 (C⁷), 127.6 (C³), 129.0 (C⁹), 130.3 (C^(5a)),131.3 (C⁶), 137.1 (C^(4a)), 138.1 (C^(11a)), 139.4 (C⁸), 143.7 (C^(9a)),156.7 (C¹), 195.2 (C5).

EXAMPLE 61 8-Chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(5)

For the synthesis of the title compound, 1.0 (4.87 mmol) g of8-chloro-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 10 ml ofHBr (48%, aqueous) and 10 ml of glacial acetic acid are employed inmethod L. Yield: 95%; m.p.: 185° C.; GC 15.2 min; C₁₅H₁₁ClO₂ (Mr=258.71)

MS m/z (%): 260/258 (34/100, M⁺), 243/241 (2/7, M⁺-OH), 232/230 (9/27,M⁺-CO), 223 (21, M⁺-Cl), 217/215 (2/7), 207/205 (2/6), 195 (28, 223-CO),177 (12), 165 (39).

IR (ATR) 3251, 2360, 1637, 1573, 1307, 1282, 1241, 1221, 1176, 1159,886, 759 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 3.07 (s, 4H, —CH₂—CH₂—), 7.04 (d, 1H, J=7.84Hz, C²—H), 7.15 (t, 1H, J=7.78 Hz, C³—H), 7.28 (d, 1H, J=7.69 Hz, C⁷—H),7.38 (d, 1H, J=8.31 Hz, C⁴—H), 7.45 (s, 1H, C⁹—H), 7.67 (d, 1H, J=8.32,C⁶—H), 9.84 (s, 1H, —OH).

¹³C-NMR (DMSO-d6) δ in ppm: 26.5 (C¹¹), 33.0 (C¹⁰), 119.1 (C²), 120.6(C⁴), 126.9 (C⁷), 127.2 (C³), 128.7 (C⁹), 129.0 (C^(5a)), 131.3 (C⁶),136.9 (C^(4a)), 138.4 (C^(11a)), 139.5 (C⁸), 143.8 (C^(9a)), 155.0 (C¹),195.4 (C⁵).

EXAMPLE 628-(2,4-Difluorophenylamino)-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(11c)

For the synthesis of the title compound, 0.52 g (0.0020) mol of8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.26 g(0.0020 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)₂, 0.14 gof phosphine ligand and 0.90 g (0.0094 mol) of NaOtert-Bu in 10 ml oftoluene and 2 ml of tert-BuOH are reacted by method O. Purification iscarried out by column chromatography (flash; silica gel, 90% hexane+10%ethyl acetate). C₂₁H₁₅F₂NO₂ (Mr=351.36); GC 35.3 min

MS m/z (%): 351 (100, M+), 336 (4, M+-O), 323 (10, M+-CO), 308 (3,323-O), 223 (2, 336-difluorobenzene), 194 (12, 223-CO), 165 (13,3-methoxy-2-methylbenzoic acid), 129 (1, difluoroaniline), 115 (1,difluoroaniline).

¹H-NMR (DMSO-d6) δ in ppm: 2.93-3.06 (m, 4H, —CH₂—CH₂—), 6.61 (s, 1H,C⁹—H), 6.71 (d, 1H, J=8.04 Hz, C^(6′)—H), 6.98 (d, 1H, J=7.84 Hz, C⁷—H),7.05-7.13 (m, 2H, C^(3′)—/C^(5′)-H), 7.24 (d, 1H, J=7.62 Hz, C²—H),7.34-7.39 (m, 2H, C³—/C⁴—H), 7.41-7.78 (m, 1H, C⁶—H), 8.46 (s, 1H,—NH—), 9.69 (s, 1H, —OH).

EXAMPLE 638-(2,4-Difluorophenylamino)-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(11a)

For the synthesis of the title compound, 0.54 g (0.0020 mol) of8-chloro-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.26 g(0.0020 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)₂, 0.14 gof phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10 ml oftoluene and 2 ml of tert-BuOH are reacted by method O. Purification iscarried out by column chromatography (flash; SiO₂; hexane 90%/ethylacetate 10%). C₂₂H₁₇F₂NO₂ (Mr=365.38)

Yield: g (%); m.p.: 216° C.; GC 31.6 min

MS m/z (%): 365 (100, M⁺), 350 (6, M⁺-CH₃), 336(8), 322 (5, 350-CO), 306(3, 322-O), 208 (11, M⁺-CO —NH-Phe), 194 (8, 208-CH₃), 178 (9, 194-O),165 (17).

IR (ATR) 3276, 1299, 1286, 1269, 1255, 1193, 1073, 966, 863, 828, 764,727, 603, 534, 496, 460, 446 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 2.94-3.08 (m, 4H, —CH₂—CH₂—), 3.82 (s, 3H,—OCH₃), 6.61 (s, 1H, C⁹—H), 6.72 (d, 1H, J=8.72 Hz, C⁷—H), 7.03-7.17-(m,2H, C^(3′)—/C^(6′)—H), 7.23-7.45-(m, 4H, C²—/C³—/C⁴—H and C^(5′)-H),7.83 (d, 1H, J=8.69, C⁶—H), 8.49 (s, 1H, NH).

¹³C-NMR (DMSO-d6) δ in ppm: 25.0 (s, C¹¹), 35.1 (s, C¹⁰), 56.4 (s,—OCH₃), 105.5 (d, J=26.6 Hz, C^(3′)), 112.2 (d, J=25.6 Hz, C^(5′)),112.6 (s, C⁷), 113.8 (s, C⁹), 114.3 (s, C²), 121.9 (s, C⁴), 125.4 (d,J=12.1 Hz, C^(1′)), 126.3 (d, J=9.6 Hz, C^(6′)), 127.3 (s, C³), 128.4(s, C^(5a)), 130.1 (s, C^(4a)), 132.9 (s, C⁶), 141.2 (s, C^(11a)), 145.2(s, C⁸), 149.3 (s, C^(9a)), 154.9 (d, J=141.2 Hz, C^(4′)), 155.8 (s,C¹), 159.8 (d, J=137.1 Hz, C^(2′)), 192.6 (s, C5).

EXAMPLE 648-(2-Aminophenylamino)-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(11b)

For the synthesis of the title compound, 0.54 g (0.0020 mol) of8-chloro-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 1.08 g(0.010 mol) of phenylenediamine, 2 spatula tips of Pd(OAc)₂, 0.14 g ofphosphine ligand and 1.60 g (0.0166 mol) of NaOtert-Bu in 10 ml oftoluene and 2 ml of tert-BuOH are reacted by method O. Purification iscarried out by column chromatography (flash; SiO₂; hexane 80%/ethylacetate 20%). C₂₂H₂₀N₂O₂ (Mr=344.42)

Yield: 46(%): m.p.: 132° C.; GC 54.5 min

MS m/z (%): 344 (100, M⁺), 329 (13, M⁺-CH₃), 315 (6, M⁺-CO), 301 (5,315-CH₂), 285 (5, 301-O), 195 (9, 301-1,2-diaminobenzene), 182 (6), 165(8,3-methoxy-2-methylbenzoic acid), 107 (13, 1,2-diaminobenzene), 80(7).

IR (ATR) 3356, 3282, 2852, 1616, 1587, 1563, 1553, 1497, 1335, 1293,1272, 1255, 1222, 1192, 1075, 826, 759, 749, 706, 540, 505, 438 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 2.93-3.02 (m, 4H, —CH₂—CH₂—), 3.81 (s, 3H,—OCH₃), 4.82 (s, 2H, —NH₂), 6.45 (s, 1H, C⁹—H), 6.59 (d, 2H, J=8.22 Hz,C^(3′)—/C^(6′)—H), 6.76 (d, 1H, J=7.66 Hz, C⁷—H), 6.89-7.02 (m, 2H,C^(4′)—/C^(5′)—H), 7.13 (d, 1H, J=7.47 Hz, C²—H), 7.21-7.37 (m, 2H,C³—/C⁴—H), 7.80-8.01 (m, 2H, —NH, C⁶—H).

¹³C-NMR (DMSO-d6) δ in ppm: 24.8 (C¹¹), 35.5 (C¹⁰), 56.4 (—OCH₃), 112.0(C⁷), 113.0 (C^(3′)), 114.1 (C⁹), 115.8 (C²), 116.8 (C^(4′)), 122.0(C^(5′)), 125.3 (C^(5a)), 126.1 (C^(6′)), 126.3 (C⁴), 126.8 (C^(4a)),127.2 (C³), 130.0 (C^(11a)), 133.2 (C⁶), 141.5 (C^(1′)), 144.0 (C^(2′)),145.4 (C^(9a)), 151.0 (C⁸), 155.6 (C¹), 191.9 (C⁵).

EXAMPLE 65(S)-8-Chloro-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(13)

For the preparation of the title compound, 0.50 g (1.9 mmol) of8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.75 g(2.6 mmol) of (R)-toluene-4-sulfonic acid2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester and 0.80 g (5.8 mmol) ofK₂CO₃ in 10 ml of dry DMF are reacted by method M. Yield: 53%;C₂₁H₂₁ClO₄ (Mr=372.85); GC 22.8 min

MS m/z (%): 374/372 (35/100, M⁺), 359/357 (6/17, M⁺-CH₃), 337 (2,M⁺-Cl), 316/314 (10/26, 359/357-CH₃), 299/297 (16/39, 316/314-OH),285/283 (3/8, 299/297-CH₂), 269 (283), 258/256 (15/6 M⁺-dioxolane), 194(12, 258/256-Cl—CO), 178 (23, 194-CO), 165 (51,3-methoxy-2-methylbenzoic acid).

IR (ATR) 2962, 2359, 1650, 1586, 1449, 1370, 1310, 1284, 1257, 1213,1177, 1156, 1057, 974, 873, 790, 761, 694, 665, 555 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 1.31 (s, 3H, —CH₃), 1.36 (s, 3H, —CH₃), 3.11(s, 4H, —CH₂—CH₂), 3.78-3.86 (m, 1H, dioxolane), 4.00-4.11 (m, 3H,dioxolane), 4.41-4.46 (m, 1H, dioxolane), 7.25-7.44 (m, 4H,C²—/C³—/C⁴—/C⁷—H), 7.47 (s, 1H, C⁹—H), 7.69 (d, 1H, J=8.34 Hz, C⁶—H).

¹³C-NMR (DMSO-d6) δ in ppm: 25.7 (—CH₃), 26.3 (—CH₃), 26.9 (C¹¹), 32.8(C¹⁰), 66.0 (C³ dioxolane), 69.8 (C¹ dioxolane), 74.1 (C² dioxolane),109.2 (—C(CH₃)₂), 116.3 (C²), 122.1 (C^(a)), 127.0 (C⁷), 127.6 (C³),129.1 (C⁹), 130.7 (C^(5a)), 131.3 (C⁶), 137.1 (C^(4a)), 138.2 (C^(11a)),139.5 (C⁸), 143.7 (C^(9a)), 155.9 (C¹), 195.2 (C⁵).

EXAMPLE 66(S)-8-(2,4-Difluorophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(11d)

For the synthesis of the title compound, 0.50 g (0.0013 mol) of(S)-8-chloro-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one,0.17 g (0.0013 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)₂,0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10ml of toluene and 2 ml of tert-BuOH are reacted by method O.

Purification is carried out by column chromatography (flash; SiO₂;hexane 80%/ethyl acetate 20%). C₂₇H₂₅F₂NO₄ (Mr=465.50); yield: 37%;m.p.: 127° C.;

IR (ATR) 3307, 2981, 1503, 1287, 1257, 1207, 1139, 1062, 1041, 864, 843,832, 810, 757, 541, 515 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 1.31 (s, 3H, —CH₃), 1.36 (s, 3H, —CH₃),2.96-3.11 (m, 4H, —CH₂—CH₂—), 3.78-3.85 (m, 1H, dioxolane), 4.04-4.14(m, 3H, dioxolane), 4.38-4.46 (m, 1H, dioxolane), 6.62-6.73 (m, 2H,C7-/C9-H), 7.08-7.43 (m, 6H, C²—/C³—/C⁴—H and C^(3′)—/C^(5′)—/C^(6′)—H),7.81 (d, 1H, J=8.72 Hz, C⁶), 8.49 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 25.1 (s, C¹⁰), 25.7 (s, —CH₃), 26.9 (s,—CH₃), 35.0 (s, C¹¹), 66.0 (s, C³ dioxolane), 69.9 (s, C¹ dioxolane),74.1 (s, C² dioxolane), 105.0 (d, J=26.4 Hz, C^(3′)), 109.2 (s,—C(CH₃)₂), 112.2 (d, J=21.8 Hz, C^(5′)), 112.6 (s, C⁷), 113.9 (s, C⁹),115.7 (s, C²), 122.3 (s, C⁴), 125.4 (d, J=15.8 Hz, C^(1′)), 126.2 (d,J=6.7 Hz, C^(6′)), 127.2 (s, C³), 128.5 (s, C^(5a)), 130.4 (s, C^(4a)),132.9 (s, C⁶), 141.3 (s, C^(11a)), 145.1 (s, C⁸), 149.3 (s, C^(9a)),154.9 (d, J=138.5 Hz, C^(4′)), 155.0 (s, C¹), 159.7 (d, J=148.2 Hz,C^(2′)), 192.6 (s, C⁵).

EXAMPLE 67(R)-8-(2,4-Difluorophenylamino)-1-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo-[a,d]cyclohepten-5-one(11f)

For the synthesis of the title compound, 0.10 g (0.215 mmol) of(S)-8-(2,4-difluorophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-oneand 0.0054 g (0.0284 mmol) of p-toluenesulfonic acid monohydrate in 6 mlof methanol and 1.5 ml of water are reacted by method N. Yield: 88%;

m.p.: 125° C.

C₂₄H₂₁F₂NO₄ (Mr=425.44)

IR (ATR) 3307, 1541, 1305, 1257, 1217, 1138, 1116, 1098, 1061, 967, 847,833, 812, 758, 601, 570, 539, 458 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 3.00-3.08 (m, 4H, —CH₂—CH₂—), 3.46-3.49 (m,2H, dihydroxypropoxy), 3.78-4.03 (m, 3H, dihydroxypropoxy), 6.63-6.73(m, 2H, C⁷—/C⁹—H), 7.04-7.41 (m, 6H, C²—/C³—/C⁴—H andC³—/C^(5′)—/C^(6′)—H), 7.80 (d, 1H, J=8.73 Hz, C⁶), 8.48 (s, 1H, —NH).

¹³C-NMR (DMSO-d6) δ in ppm: 25.2 (s, C¹¹), 35.0 (s, C¹⁰), 63.1 (s, C³dihydroxypropoxy), 70.4 (s, C² dihydroxypropoxy), 70.9 (s, C¹dihydroxypropoxy), 105.3 (t, J=25.3 Hz, C^(3′)), 112.1 (d, J=25.9 Hz,C^(5′)), 112.5 (s, C⁷), 113.9 (s, C⁹), 115.5 (s, C²), 121.9 (s, C⁴),125.4 (d, J=15.6 Hz, C^(1′)), 126.1 (d, J=9.6 Hz, C^(6′)), 127.2 (s,C³), 128.6 (s, C^(5a)), 130.5 (s, C^(4a)), 132.8 (s, C⁶), 141.2 (s,C^(11a)), 145.1 (s, C⁸), 149.2 (s, C^(9a)), 154.8 (d, J=141.5 Hz,C^(4′)), 155.5 (s, C¹), 159.7 (d, J=136.2 Hz, C^(2′)), 192.7 (s, C⁵).

EXAMPLE 68(S)-8-(2-Aminophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(11e)

For the synthesis of the title compound, 0.50 g (0.0013 mol) of(S)-2-chloro-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one,0.70 g (0.0065 mol) of phenylenediamine, 2 spatula tips of Pd(OAc)₂,0.14 g of phosphine ligand and 1.04 g (0.0108 mol) of NaOtert-Bu in 10ml of toluene and 2 ml of tert-BuOH are reacted by method O.

Purification is carried out by column chromatography (flash; SiO₂;hexane 70%/ethyl acetate 30%). Yield: 23%; m.p.: <35° C.; C₂₇H₂₈N₂O₄(Mr=444.54)

IR (ATR) 3347, 2927, 1566, 1499, 1450, 1254, 1212, 1155, 1069, 969, 908,832, 745, 703, 599, 512, 448 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 1.31 (s, 3H, —CH₃), 1.36 (s, 3H, —CH₃),2.91-3.10 (m, 4H, —CH₂—CH₂—), 3.78-3.85 (m, 1H, dioxolane), 4.00-4.03(m, 3H dioxolane), 4.40-4.43 (m, 1H, dioxolane), 4.82 (s, 2H, —NH₂),6.47-6.62 (m, 3H, C⁹—H and C^(5′)—/C^(6′)—H), 6.78 (d, 1H, J=7.29 Hz,C^(3′)—H), 6.92 (d, 1H, J=7.17 Hz, C⁷—H), 7.01 (d, 1H, J=7.76 Hz, C²—H),7.16-7.24 (m, 2H, C³—H and C^(4′)—H), 7.38 (d, 1H, J=7.55 Hz, C⁴—H),7.82 (d, 1H, J=8.74, C⁶—H), 7.91 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 24.9 (C¹¹), 25.7 (—CH₃), 26.9 (—CH₃), 35.4(C¹⁰), 66.0 (C³ dioxolane), 69.9 (C¹ dioxolane), 74.1 (C² dioxolane),109.2 (—C(CH₃)₂), 112.0 (C⁷), 113.1 (C⁹), 115.5 (C^(3′)), 115.8 (C²),116.8 (C^(4′)), 122.4 (C^(5′)), 125.3 (C^(5a)), 126.0 (C^(6′)), 126.3(C⁴), 126.9 (C³), 127.2 (C^(4a)), 130.4 (C^(11a)), 133.1 (C⁶), 141.6(C^(1′)), 193.9 (C^(2′)), 145.3 (C⁸), 150.9 (C^(9a)), 154.9 (C¹), 191.9(C⁵).

EXAMPLE 69(R)-8-(2-Aminophenylamino)-1-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclo-hepten-5-one(11g)

For the synthesis of the title compound, 0.10 g (0.225 mmol) of(S)-8-(2-aminophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-oneand 0.0537 g (0.282 mmol) of p-toluenesulfonic acid monohydrate in 6 mlof methanol and 1.5 ml of water are reacted by method N. C₂₄H₂₄N₂O₄(Mr=404.47); yield: 40%

IR (ATR) 3305, 2919, 1566, 1498, 1449, 1255, 1216, 1189, 1155, 1111,1043, 967, 908, 831, 749, 703, 448, 405 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 2.93-3.11 (m, 4H, —CH₂—CH₂—), 3.47 (d, 2H,J=5.48 Hz, C³—H dihydroxypropoxy), 3.83 (q, 1H, J=5.60 Hz, C²—Hdihydroxypropoxy), 3.85-4.06 (m, 2H, C¹—H dihydroxypropoxy), 4.82 (s,2H, —NH₂), 6.48 (s, 1H, C⁹—H), 6.59 (d, 2H, J=7.39 Hz,C^(3′)—/C^(6′)—H), 6.76 (d, 1H, J=7.41 Hz, C⁷—H), 6.90-7.02 (m, 2H, C⁴—Hand C^(5′)-H), 7.12 (d, 1H, J=7.37 Hz, C²—H), 7.23 (t, 1H, J=7.80 Hz,C³—H), 7.34 (d, 1H, J=7.09 Hz, C⁴—H), 7.80 (d, 1H, J=8.74 Hz, C⁶—H),7.91 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 25.0 (C¹¹), 35.4 (C¹⁰), 63.1 (C³dihydroxypropoxy), 70.4 (C² dihydroxypropoxy), 70.9 (C¹dihydroxypropoxy), 112.0 (C⁷), 113.2 (C⁹), 115.4 (C^(3′)), 115.8 (C²),116.8 (C^(4′)), 122.0 (C^(6′)), 125.4 (C^(5a)), 126.0 (C^(5′)), 126.3(C⁴), 127.0 (C³), 127.1 (C^(4a)), 130.5 (C^(11a)), 133.1 (C⁶), 141.5(C^(1′)), 143.9 (C^(2′)), 145.3 (C⁷), 150.9 (C^(9a)), 155.3 (C¹), 192.1(C⁵).

EXAMPLE 708-Chloro-1-(tetrahydropyran-4-yloxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(15)

For the synthesis of the title compound, 0.45 g (1.7 mmol) of8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.28 g(0.0027 mol) of tetrahydropyran-4-ol, 0.77 g (2.9 mmol) of P(Ph)₃ and0.41 g (2.0 mmol) of diisopropyl azodicarboxylate in 2 ml of THF arereacted by method P. C₂₀H₁₉ClO₃ (Mr=342.83); yield: 45%

¹H-NMR (DMSO-d6) δ in ppm: 1.63 (s, 2H, C²—H pyran), 1.91 (s, 2H, C⁶—Hpyran), 3.10 (s, 4H, —CH₂—CH₂—), 3.48 (s, 2H, C³—H pyran), 3.79 (s, 2H,C⁵—H pyran), 4.61 (s, 1H, C¹—H pyran), 7.05-7.42 (m, 5H,C²—/C³—/C⁴—/C⁶—/C⁷—H), 7.67 (s, 1H, C⁹—H).

¹³C-NMR (DMSO-d6) δ in ppm: 26.4 (C¹¹), 31.9 (2C, C²/C⁶ pyran), 32.9(C¹⁰), 64.6 (2C, C³/C⁵ pyran), 72.4 (C¹ pyran), 118.1 (C²), 122.1 (C⁴),127.0 (C⁷), 127.4 (C³), 129.1 (C⁹), 131.4 (C⁶), 137.1 (C^(4a)), 138.0(C^(5a)), 139.9 (C^(11a)), 143.8 (C⁸), 154.3 (C^(9a)), 156.5 (C¹), 195.2(C⁵).

EXAMPLE 718-(2,4-Difluorophenylamino)-1-(tetrahydropyran-4-yloxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(11 h)

For the synthesis of the title compound, 0.45 g (0.0013 mol) of8-chloro-1-(tetrahydropyran-4-yloxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one,0.17 g (0.0013 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)₂,0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10ml of toluene and 2 ml of tert-BuOH are reacted by method O.Purification is carried out by column chromatography (flash; SiO₂;hexane 70%/ethyl acetate 30%).

C₂₆H₂₃F₂NO₃ (Mr=435.47); yield: 52%; m.p.: 134° C.

IR (ATR) 3327, 2961, 2857, 1564, 1496, 1300, 1277, 1257, 1243, 1187,1150, 1131, 1099, 1088, 1005, 957, 858, 833, 813, 769, 630, 577, 550,508 cm⁻¹.

¹H-NMR (DMSO-d6) δ in ppm: 1.54-1.71 (m, 2H, C²—H pyran), 1.91-2.00 (m,2H, C⁶—H pyran), 2.96-3.12 (m, 4H, —CH₂—CH₂—), 3.43-3.54 (m, 2H, C³—Hpyran), 3.78-3.88 (m, 2H, C⁴—H pyran), 4.59 (q, 1H, J=3.68 Hz, C¹—Hpyran), 6.62 (s, 1H, C⁹—H), 6.71 (d, 1H, J=8.68 Hz, C⁷—H), 7.03-7.13 (m,1H, C^(6′)—H), 7.22-7.25 (m, 2H, C^(3′)—/C^(6′)—H), 7.29-7.42 (m, 3H,C²—/C³—/C⁴—H), 7.82 (d, 1H, J=8.66 Hz, C⁶—H), 8.48 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 25.3 (s, C¹¹), 32.0 (s, 2C, C²/C⁶ pyran),35.1 (s, C¹⁰), 64.7 (s, 2C, C³/C⁵ pyran), 72.8 (s, C¹ pyran), 105.3 (t,J=25.5 Hz, C^(3′)), 112.2 (d, J=22.1 Hz, C^(5′)), 112.7 (s, C⁷), 113.9(s, C⁹), 117.9 (s, C²), 122.4 (s, C⁴), 125.4 (d, J=15.7 Hz, C^(1′)),126.2 (d, J=9.5 Hz, C^(6′)), 127.1 (s, ^(C3)), 128.4 (s, C^(5a)), 131.5(s, C^(4a)), 132.9 (s, C⁶), 141.7 (s, C^(11a)), 145.2 (s, C⁸), 149.2 (s,C^(9a)), 155.0 (d, J=141.0 Hz, C^(4′)), 153.4 (s, C¹), 159.6 (d, J=137.2Hz, C^(2′)), 192.6 (s, C⁵).

EXAMPLE 728-Chloro-1-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(16)

For the synthesis of the title compound, 0.44 g (1.69 mmol) of8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.345 g(1.86 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.93 g(6.75 mmol) of K₂CO₃ in 15 ml of acetonitrile are reacted by method Q.C₂₁H₂₁ClNO₃ (Mr=371.87); GC 29.7 min

MS m/z (%): 373/371 (1/4, M⁺), 165 (4,3-methoxy-2-methyl-benzoic acid),114 (1, ethylmorpholine), 100 (100, 114-CH₂), 87 (1, 100-CH₂).

IR (ATR) 2854, 1585, 1451, 1282, 1252, 1115, 1090, 1062, 909, 860, 757cm⁻¹

¹H-NMR (DMSO-d6) δ in ppm: 2.50 (under DMSO, 4H, C²—/C⁶—H morpholine),2.71 (t, 2H, J=5.61 Hz, C²—H ethylmorpholine), 3.09 (s, 4H, —CH₂—CH₂—cycloheptane), 3.47-3.58 (m, 4H, C³—/C⁵—H morpholine), 4.12 (t, 2H,J=5.59 Hz, C¹—H ethylmorpholine), 7.23-7.70 (m, 6H,C²—/C³—/C⁴—/C⁶—/C⁷—/C⁹—H).

¹³C-NMR (DMSO-d6) δ in ppm: 26.4 (C¹¹), 32.9 (C¹⁰), 53.9 (C²/C⁶morpholine), 57.3 (C² ethylmorpholine), 66.6 (C³/C⁵ morpholine), 67.0(C¹ ethylmorpholine), 116.3 (C²), 121.9 (C⁴), 127.0 (C⁷), 127.5 (C³),129.1 (C⁹), 130.7 (C⁶), 131.3 (C^(5a)), 137.1 (C^(4a)), 138.1 (C^(11a)),139.5 (C⁸), 143.7 (C^(9a)), 156.0 (C¹), 195.2 (C⁵).

EXAMPLE 738-(2,4-Difluorophenylamino)-1-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclo-hepten-5-one(11j)

For the synthesis of the title compound, 0.48 g (0.0013 mol) of8-chloro-1-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one,0.17 g (0.0013 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)₂,0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10ml of toluene and 2 ml of tert-BuOH are reacted by method O.Purification is carried out by column chromatography (flash; SiO₂;hexane 60%/ethyl acetate 40%).

C₂₇H₂₆F₂N₂O₃ (Mr=464.52)

¹H-NMR (DMSO-d6) δ in ppm: 2.49 (under DMSO, 4H C²—/C⁶—H morpholine),2.72 (t, 2H, J=5.62 Hz, C²—H ethylmorpholine), 2.99-3.10 (m, 4H,—CH₂—CH₂— cycloheptane), 3.56 (t, 4H, J=4.58 Hz, C³—/C⁵—H morpholine),4.12 (t, 2H, J=5.62 Hz, C¹—H ethylmorpholine), 6.62 (s, 1H, C⁹—H), 6.71(d, 1H, J=8.68 Hz, C⁷—H), 7.08-7.41 (m, 6H, C²—/C³—/C⁴—H andC^(3′)—/C^(6′)—/C^(6′)—H), 7.82 (d, 1H, J=8.67 Hz, C⁶—H), 8.48 (s, 1H,—NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 25.2 (s, C¹¹), 35.1 (s, C¹⁰), 53.9 (s, 2C,C²/C⁶ morpholine), 57.4 (s, C² ethylmorpholine), 66.6 (s, 2C, C³/C⁵morpholine), 67.1 (s, C¹ ethylmorpholine), 105.3 (dd, J₁=26.6 Hz,J₂=24.1 Hz, C^(3′)), 112.1 (dd, J₁=21.8 Hz, J₂=3.7 Hz, C^(5′)), 112.6(s, C⁷), 113.9 (s, C⁹), 115.8 (s, C²), 122.1 (s, C⁴), 125.4 (dd, J₁=12.1Hz, J₂=3.6 Hz, C^(1′)), 126.2 (dd, J₁=9.6 Hz, J₂=3.2 Hz, C^(6′)), 127.2(s, C^(5a)), 128.5 (s, C³), 130.5 (s, C^(4a)), 132.9 (s, C⁶), 141.3 (s,C^(11a)), 145.1 (s, C⁸), 149.2 (s, C^(9a)), 154.8 (dd, J₁=140.7 Hz,J₂=12.6 Hz, C^(4′)), 155.1 (s, C¹), 159.7 (dd, J₁=136.5 Hz, J₂=11.8 Hz,C^(2′)), 196.6 (s, C⁵).

EXAMPLE 74 Trifluoromethanesulfonic acid8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl ester

For the preparation of the title compound, 0.517 g (0.0020 mol) of8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one and 0.846g (0.0030 mol) of Tf₂O in 5 ml of pyridine are reacted by method R.C₁₆H₁₀ClF₃O₄S (Mr=390.77); GC 11.9 min

MS m/z (%): 392/390 (39/100, M⁺), 364/362 (9/24, M⁺-CO), 259/257 (17/50,M⁺-SO₂CF₃), 231/229 (10/31, 259/257-CO), 194 (54, 231/229-Cl).

C. Dibenzooxoepinones Substituted at Position 8 Material and Methods

Melting points: Buchi Melting Point B-545 (thermodynamic correction)NMR spectroscopy: Bruker Advance 200 (200 MHz)Internal standard: Tetramethylsilane (TMS), δ [ppm]=0IR spectroscopy: Perkin Elmer Spectrum One (ATR technique)TLC: SiO₂ 60 F₂₅₄-Alu film, Merck familyGC/MS: Hewlett Packard HP 6890 Series GC-System (column: HP-5MS: 5%phenyl-methyl-siloxane; length: 30.0 m, diameter: 250 μm, filmthickness: 0.25 μm; or similar column from other manufacturersCarrier gas: Helium 6.0; flow rate: 1.2 ml/min

Hewlett Packard HP 5973 Mass Selective Detector Method 1:

Injection temperature: 250° C.

Heating rate [K/min] End temperature [° C.] Holding time [min] 100 1 10160 10 15 200 15

Method 2:

Injection temperature: 250° C.

Heating rate [K/min] End temperature [° C.] Holding time [min] 100 1 10160 10 15 200 15 10 270 20

Method 3:

Injection temperature: 250° C.

Heating rate [K/min] End temperature [° C.] Holding time [min] 160 1 10240 5 10 270 15

Method 3_L:

Injection temperature: 250° C.

Heating rate [K/min] End temperature [° C.] Holding time [min] 160 1 10240 5 10 270 30

LC/MS: TSQ Quantum Surveyor HPLC (Thermo Finnigan, Calif., San Jose)

binary pump/autosampler/PDA detectorcoupled to Thermo Finnigan TSQ Quantum triple quadrupole MS

General Synthesis Methods General Method S

For esterification of the acid group of the starting compound2-methyl-4-nitro-benzoic acid, the stated amount is dissolved inmethanol in a 100 ml one-necked flask at room temperature, concentratedH₂SO₄ is added and the mixture is refluxed at approx. 60° C. for 6 h.The excess alcohol is removed in vacuo, the residue is taken up in EtOAcand the mixture is deacidified repeatedly with 20% strength sodiumhydroxide solution. After drying (Na₂SO₄), the combined organic phasesare concentrated in vacuo.

General Method T

The substance to be halogenated is dissolved in carbon tetrachloride ina 250 ml three-necked flask with a reflux condenser and drying tube atapprox. 70° C. and the stated amounts of N-bromosuccinimide andazobisisobutyronitrile are added. The mixture is refluxed for 5 h, ifnecessary with irradiation with a 500 W spotlight. At the end of thereaction, the N-bromosuccinimide has dissolved and has been convertedinto succinimide, which settles on the surface. After cooling to roomtemperature, the mixture is filtered with suction. The filtrate isevaporated on a rotary evaporator in order to obtain the product as ayellow-orange oil.

General Method U

For further reaction of the brominated educt with substituted phenols,the stated amount of potassium carbonate is suspended in acetone in a250 ml three-necked flask. The phenol to be deprotonated is added andthe mixture is stirred at room temperature for 15 min. The brominatedbenzoic acid methyl ester is then added to the mixture and, afterheating to 70° C., the mixture is refluxed for 6 h. The acetone isremoved in vacuo and the residue is extracted by shaking several timeswith EtOAc. After acidification of the aqueous phase with 20% strengthHCl, the combined organic phases are concentrated in vacuo after drying(Na₂SO₄) and the residue is purified by recrystallization with methanol.

General Method V

The carboxylic acid ester to be hydrolyzed is dissolved in methanol in a100 ml one-necked flask at room temperature, while stirring, and thestated amount of aqueous KOH solution is then added. After heating to40° C., the mixture is refluxed for 4 h. The excess alcohol is removedin vacuo and the residue is taken up with H₂O. Acidification of theaqueous phase with 20% strength HCl and subsequent stirring on icefollow, and the crude product obtained by this procedure is filtered offwith suction and dried over calcium chloride.

General Method W

For the synthesis of the ketones, the stated amount of carboxylic acidis suspended in sulfolane in a dry 250 ml three-necked flask under anargon atmosphere and while heating. Polyphosphoric acid is added and themixture is refluxed at 100° C. for approx. 2 h. After cooling to roomtemperature, the mixture is poured into 250 ml of ice-water andsubsequently stirred at RT. The crude product which has precipitated outis filtered off.

General Method X

The acetylated ring system is dissolved in methanol by heating in a 100ml one-necked flask with a reflux condenser, and the stated amount ofconcentrated hydrochloric acid is then added. The reaction mixture isstirred under reflux for 4 h. The mixture is then concentrated in vacuo.Hydrochloric acid (10%) is added to the residue and the mixture isstirred up and then placed on ice, and after waiting until the producthas crystallized out completely, this is filtered off.

General Method Y

For reduction of the nitro compound, the stated amount of tin(II)chloride dihydrate is dissolved in ethanol, while stirring. The nitrocompound to be reduced is added and the mixture is refluxed at 100° C.for 2 h. After cooling to room temperature, ice-water is added to themixture and the mixture is rendered alkaline with 20% strength sodiumhydroxide solution. Repeated extraction with ethyl acetate is carriedout; after drying (Na₂SO₄), the combined organic phases are concentratedin vacuo.

General Method Z

The stated amounts of 3-amino-8-nitro-6H-dibenzo[b,e]oxepin-11-one,phosphine ligand, KOt-Bu, tert-butanol, haloaromatic, Pd(OAc)₂ areweighed into a dry 100 ml three-necked flask with a reflux condenser,bubble counter and thermometer. The mixture is suspended in toluene(anhydrous) under an argon atmosphere and the suspension is heated to110° C. and refluxed for 2 h. Hydrolysis with ice-water and repeatedextraction with EtOAc are carried out. The combined organic phases arefiltered and then concentrated in vacuo. The residue is purified bychromatography.

EXAMPLE 75 2-Methyl-4-nitro-benzoic acid methyl ester (1)

In accordance with general method S, 5.00 g (27.60 mmol) of2-methyl-4-nitro-benzoic acid are dissolved in 20 ml of methanol, withheating, and 6 ml of concentrated sulfuric acid are added. The mixtureis refluxed for 5 h. Yield: 4.90 g (90.9%); melting point: 73.6° C.

C₉H₉NO₃(M_(r)=195.18); GC (method 1) 9.55 min

¹H-NMR (CDCl₃)

in ppm: 8.19-8.09 (m, 2H, aryl H), 7.99 (d, 1H, J=8.52 Hz, aryl H), 3.87(s, 3H, —OCH₃), 2.59 (s, 3H, —CH₃)

¹³C-NMR (CDCl₃)

in ppm: 166.35 (—C═O), 159.29 (C⁴), 141.79 (C²), 135.14 (C¹), 131.43(C⁶), 126.06 (C³), 120.48 (C⁵), 52.37 (—OCH₃), 21.50 (—CH₃)

IR (ATR) (cm⁻¹): 1722, 1523, 1432, 1348, 1260, 1081, 896, 821, 786, 730

MS m/z (%): 195 (70), 164 (100), 134 (21), 118 (29), 63 (15)

EXAMPLE 76 2-Bromomethyl-4-nitro-benzoic acid methyl ester (2)

In accordance with general method T, 4.70 g (24.00 mmol) of (1) aredissolved in 30 ml of carbon tetrachloride, with heating, and 5.00 g(28.00 mmol) of N-bromosuccinimide and 2 spatula tips ofazobisisobutyronitrile are then added. The mixture is refluxed for 6 hwith irradiation with a 500 W spotlight. On cooling to room temperature,succinimide separates out, and is filtered off. The filtrate isevaporated on a rotary evaporator in order to obtain the product as ayellow oil. Yield: 5.85 g (88.8%)

C₉H₈BrNO₄ (M_(r)=274.07); GC (method 3) 7.98 min

¹H-NMR (CDCl₃)

in ppm: 4.96 (s, 2H, —CH₂—Br), 2.71 (s, 3H, —CH₃)

MS m/z (%): 274 (100), 193 (38), 178 (46), 147 (12), 132 (18), 88 (9)

EXAMPLE 77 2-(3-Acetylaminophenoxymethyl)-4-nitrobenzoic acid methylester (3)

In accordance with general method U, 1.50 g (10.86 mmol) of potassiumcarbonate are suspended in 15 ml of acetone, 1.80 g (11.90 mmol) of3-acetamidophenol are then added and the mixture is stirred for 15 min.2.44 g (8.91 mmol) of (2) are added to the mixture.

Yield: 1.33 g (43.3%); melting point: 139.2° C.

C₁₇H₁₆N₂O₆ (M_(r)=344.33); GC (method 3) 23.07 min

¹H-NMR (DMSO-_(d6))

in ppm: 9.95 (s, 1H, —NH), 8.45 (d, 1H, J=1.98 Hz, aryl H), 8.27 (m, 1H,aryl H), 8.12 (d, 1H, J=8.54 Hz, aryl H), 7.37 (s, 1H, aryl H),7.21-7.16 (m, 2H, aryl H), 6.71-6.68 (m, 1H, aryl H), 5.44 (s, 2H,—CH₂—O), 3.86 (s, 3H, —O—CH₃)

¹³C-NMR (DMSO-_(d6))

in ppm: 168.75 (—NH—C═O—), 166.00 (—C═O), 158.41 (C^(1′)), 149.75 (C⁴),141.00 (C²), 140.77 (C^(3′)), 134.48 (C¹), 132.10 (C⁶), 130.02 (C^(5′)),123.08 (C³), 122.64 (C⁵), 112.37 (C^(4′)), 109.49 (C^(6′)), 105.94(C^(2′)), 65.01 (—CH₂—O), 52.16 (—O—CH₃), 24.41 (—NH═O—CH₃)

IR (ATR) (cm⁻¹): 1729, 1719, 1606, 1349, 1289, 1253, 1158, 1057, 771,727

MS m/z (%): 344 (10), 327 (10), 271 (3), 194 (100), 148 (44)

EXAMPLE 78 2-(3-Acetylaminophenoxymethyl)-4-nitrobenzoic acid (4)

In accordance with general method V, 1.30 g (3.78 mmol) of (3) aredissolved in 20 ml of methanol, and 0.70 g (12.50 mmol) of KOH areadded. Yield 1.20 g (96.1%); melting point: 225.0° C.; C₁₆₇H₁₄N₂O₆(M_(r)=330.30)

¹H-NMR (DMSO-_(d6))

in ppm: 9.96 (s, 1H, —COOH), 8.42 (d, 1H, J=2.06 Hz, aryl H), 8.26 (dd,1H, J₁=8.52 Hz, J₂=2.38 Hz, aryl H), 8.13 (d, 1H, J=8.00 Hz, aryl H),7.37 (s, 1H, aryl H), 7.26-7.14 (m, 2H, aryl H), 6.72-6.66 (m, 1H, arylH), 5.47 (s, 2H, —CH₂—O), 2.01 (s, 3H, —CH₃)

¹³C-NMR (DMSO-_(d6))

in ppm: 168.74 (—COOH), 167.14 (—NH—C═O), 158.46 (C^(I)), 149.58 (C⁴),141.00 (C²), 140.81 (C^(3′)), 135.63 (C¹), 132.27 (C⁶), 130.02 (C^(5′)),122.89 (C³), 122.28 (C⁵), 112.30 (C^(4′)), 109.55 (C^(6′)), 105.90(C^(2′)), 67.10 (—CH₂—O—), 24.40 (—NH—C═O—CH₃)

IR (ATR) (cm⁻¹): 1732, 1603, 1520, 1487, 1343, 1284, 1159, 1053, 767,733

EXAMPLE 79 3-Acetamido-8-nitro-6H-dibenzo[b,e]oxepin-11-one (5)

In accordance with general method W, 0.80 g (2.42 mmol) of (4) is partlydissolved in 10 ml of sulfolane at 100° C. 15 ml (30.0 g) ofpolyphosphoric acid are then added to the reaction mixture. Yield: 0.50g (66.2%); melting point: 171.4° C.

C₁₆H₁₂N₂O₅ (M_(r)=312.28); LC 18.62 min

¹H-NMR (DMSO-_(d6))

in ppm: 9.95 (s, 1H, —NH), 8.42 (d, 1H, J=2.32 Hz, aryl H), 8.51 (dd,1H, J₁=17.4 Hz, J₂=2.36 Hz, aryl H), 8.13 (d, 1H, J=8.56 Hz, aryl H),7.36 (s, 1H, aryl H), 7.21 (s, 1H, aryl H), 7.17 (s, 1H, aryl H),6.72-6.66 (m, 1H, aryl H), 5.47 (s, 2H, —CH₂—O)

IR (ATR) (cm⁻¹): 1670, 1580, 1526, 1406, 1344, 1294, 1247, 905, 740, 708

MS (ESI) 312.9 [M+H]⁺

EXAMPLE 80 3-Amino-8-nitro-6H-dibenzo[b,e]oxepin-11-one (6)

In accordance with general method X, 0.70 g (2.24 mmol) of (5) isdissolved in 25 ml of methanol, and 8.0 ml of concentrated sal acid areadded. Yield: 0.40 g (66.1%); melting point: 59.0° C.; C₁₄H₁₀N₂O₄(M_(r)=270.25); GC (method 3) 20.74 min

¹H-NMR (DMSO-_(d6))

in ppm: 8.45 (d, 1H, J=2.10 Hz, aryl H), 8.30 (dd, 1H, J₁=2.54 Hz,J₂=2.35 Hz, aryl H), 7.99 (d, 1H, J=8.58 Hz, aryl H), 7.87 (d, 1H,J=8.90 Hz, aryl H), 6.42 (dd, 1H, J₁=2.89 Hz, J₂=2.14 Hz, aryl H), 6.10(d, 1H, J=2.0 Hz, aryl H), 5.29 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO-_(d6))

in ppm: 185.21 (C¹¹), 163.65 (C^(4a)), 162.24 (C³), 157.01 (C⁸), 154.81(C^(6a)), 137.84 (C^(10a)), 134.01 (C¹), 131.02 (C¹⁰), 123.91 (C⁷),123.38 (C⁹), 114.37 (C^(11a)), 110.98 (C²), 100.98 (C⁴), 71.90 (C⁶)

IR (ATR) (cm⁻¹): 2790, 2565, 1644, 1608, 1531, 1297, 1250, 1150, 1085,907, 819, 708

MS m/z (%): 270 (100), 241 (13), 224 (14), 195 (22), 167 (19), 139 (10),83 (9), 63 (9)

EXAMPLE 813-(2,4-Difluorophenylamino)-8-nitro-6H-dibenzo[b,e]oxepin-11-one (7)

In accordance with general method Z, 0.50 g (1.85 mmol) of (6), 0.28 g(1.89 mmol) of 1-chloro-2,4-difluorobenzene, 2 spatula tips of Pd(OAc)₂,0.09 g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl(phosphine ligand), 0.50 g of KOt-Bu, 1.5 ml of t-BuOH are weighed outand dissolved in 10 ml of toluene (anhydrous). The mixture is refluxedat 100° C. under an argon atmosphere for 4 h. The crude product ispurified by chromatography over silica gel with MC/EtOH (98/2). Yield:0.05 g (7.0%); melting point: 210-214° C.

C₂₀H₁₂F₂N₂O₄ (M_(r)=382.33); LC 8.97 min

¹H-NMR (DMSO-_(d6)) δ in ppm: 8.84 (s, 1H, aryl H), 8.48 (d, 1H, J=2.01Hz, aryl H), 8.30 (m, 1H, aryl H), 8.01 (dd, 2H, J₁=2.70 Hz, J₂=3.25 Hz,aryl H), 7.47-7.33 (m, 2H, aryl H), 7.15-7.04 (m, 2H, aryl H), 6.63 (d,1H, J=10.0 Hz, aryl H), 6.24 (s, 1H, aryl H), 5.34 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO-_(d6))

in ppm: 186.11 (C¹¹), 163.30 (C^(4a)), not detected (C4′, C2′), 152.89(C⁸), 149.52 (C³), 145.34 (C^(6a)), 137.76 (C^(10a)), 133.85 (C¹),131.01 (C¹⁰), 127.38 (C^(1′), J=9.85 Hz), 124.23 (C^(6′), J=14.23 Hz),116.52 (C⁷), 112.57 (C^(5′), J=3.52 Hz), 110.35 (C²), 105.45 (C^(3′),J=24.29 Hz), 101.93 (C⁴), 72.03 (C⁶)

IR (ATR) (cm⁻¹): 2849, 1643, 1608, 1531, 1297, 1249, 1150, 740

MS (ESI) 381.1 [M−H]⁻

EXAMPLE 823-(2,4-Difluorophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one (8)

In accordance with general method Y, 0.10 g (0.44 mmol) of tin(II)chloride dihydrate is dissolved in 7 ml of ethanol, and 0.45 g (0.11mmol) of (7) is added. Yield: 0.035 g (90.3%); melting point: 184-193°C.; C₂₀H₁₄F₂N₂O₂ (M_(r)=282.30); LC 7.76 min

¹H-NMR (DMSO-_(d6))

in ppm: 8.60 (s, 1H, —NH), 8.01 (d, 1H, J=10.00 Hz, aryl H), 7.66 (d,1H, J=8.0 Hz, aryl H), 7.46-7.30 (m, 2H, aryl H), 7.13-7.04 (m, 1H, arylH), 6.58 (d, 2H, J=12.0 Hz, aryl H), 6.55 (s, 1H, aryl H), 6.46 (s, 1H,aryl H), 6.06 (s, 2H, —NH₂), 4.97 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO-_(d6))

in ppm: 184.59 (C¹¹), 162.65 (C^(4a)), not detected (C^(4′), C^(2′))153.51 (C⁸), 151.07 (C³), 139.19 (C^(6a)), 133.86 (C¹), 132.47 (C¹⁰),127.02 (C⁹), 126.99 (C^(1′)), 125.55 (C^(6′)), 118.32 (C^(10a)), 113.50(C⁷), 111.67 (C^(5′)), 109.85 (C²), 105.32 (C^(3′)), 102.56 (C⁴), 74.41(C⁶)

IR (ATR) (cm⁻¹): 1613, 1586, 1557, 1523, 1402, 1324, 1312, 1281, 1258,1115, 816

MS (ESI) 353.2 [M+H]⁺

EXAMPLE 83 3-(2-Nitrophenylamino)-8-nitro-6H-dibenzo[b,e]oxepin-11-one(9)

In accordance with general method Z, 1.00 g (3.70 mmol) of (6), 0.80 g(3.96 mmol) of 1-bromo-2-nitrobenzene, 2 spatula tips of Pd(OAc)₂, 0.10g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphineligand), 0.70 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out anddissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at100° C. under an argon atmosphere for 4 h. The crude product is purifiedby chromatography over silica gel with MC/EtOH (98/2). Yield 0.35 g(24.2%); melting point: 212.5° C.

C₂₀H₁₃N₃O₆ (M_(r)=391.34); LC9.18 min

¹H-NMR (DMSO-_(d6))

in ppm: 9.34 (s, 1H, —NH), 8.50 (d, 1H, J=2.24 Hz, aryl H), 8.34 (dd,1H, J₁=2.39 Hz, J₂=2.40 Hz, aryl H), 8.10-7.98 (m, 3H, aryl H),7.66-7.56 (m, 2H, aryl H), 7.25 (t, 1H, J₁=1.6 Hz, J₂ ⁼6.8 Hz, aryl H),6.97 (dd, 1H, J₁=2.04 Hz, J₂=2.23 Hz, aryl H), 6.71 (s, 1H, aryl H),5.39 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO-_(d6))

in ppm: 184.34 (C¹¹), 162.90 (C^(4a)), 149.93 (C⁸), 149.69 (C³), 145.19(C^(6a)), 137.69 (C^(10a)), 136.34 (C^(1′)), 135.45 (C^(5′)), 134.08(C^(2′)), 133.68 (C¹), 130.99 (C¹⁰), 128.40 (C^(3′) and C⁷), 126.40(C^(6′)), 123.66 (C⁹), 123.33 (C^(4′)), 118.55 (C^(11a)), 112.45 (C²),106.36 (C⁴), 72.34 (C⁶)

IR (ATR) (cm⁻¹): 1642, 1595, 1582, 1500, 1356, 1340, 1269, 1248, 1226,1152, 1131, 1034, 736

MS (ESI) 390.3 [M−H]⁻

EXAMPLE 84 3-(2-Aminophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one(10)

In accordance with general method Y, 2.40 g (10.66 mmol) of tin(II)chloride dihydrate are dissolved in 15 ml of ethanol, and 0.35 g (0.89mmol) of (9) is added. Yield: 0.20 g (67.9%);

melting point: 203.9° C.; C₂₀H₁₇N₃O₂ (M_(r)=331.38); LC 7.05 min

¹H-NMR (MeOH-_(d4))

in ppm: 8.09 (d, 1H, J=9.0 Hz, aryl H), 7.78 (d, 1H, J=8.55 Hz, aryl H),7.09-7.00 (m, 2H, aryl H), 6.89-6.88 (m, 1H, aryl H), 6.71-6.64 (m, 2H,aryl H), 6.55-6.49 (m, 2H, aryl H), 6.14 (d, 1H, J=2.26 Hz, aryl H),4.97 (s, 2H, —CH₂—O)

¹³C-NMR (MeOH-_(d4))

in ppm: 186.65 (C¹¹), 163.58 (C^(4a)), 153.31 (C⁸), 153.12 (C³), 143.31(C^(6a)), 139.37 (C^(I)), 133.34 (C¹), 131.97 (C¹⁰), 127.65 (C^(6′)),126.51 (C^(2′)), 125.66 (C^(10a)), 117.775 (C^(5′)), 116.89 (C^(11a)),115.96 (C^(4′)), 113.34 (C⁹), 111.46 (C^(3′)), 109.27 (C²), 101.14 (C⁴),73.99 (C⁶)

IR (ATR) (cm⁻¹): 1601, 1579, 1550, 1497, 1291, 1267, 1228, 1112, 828,757, 747

MS (ESI) 332.9 [M+H]⁺

EXAMPLE 853-(4-Fluoro-2-nitrophenylamino)-8-nitro-6H-dibenzo[b,e]oxepin-11-one(11)

In accordance with general method Z, 0.85 g (3.14 mmol) of (6), 0.70 g(3.19 mmol) of 1-bromo-4-fluoro-2-nitrobenzene, 2 spatula tips ofPd(OAc)₂, 0.10 g of2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphineligand), 0.70 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out anddissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at100° C. under an argon atmosphere for 4 h. The crude product is purifiedby chromatography over silica gel with MC/EtOH (98/2). Yield: 0.10 g(7.8%); melting point 210.7° C.

C₂₀H₁₂FN₂O₄ (M_(r)=409.33); LC 9.15 min

¹H-NMR (DMSO-_(d6))

in ppm: 9.22 (s, 1H, —NH), 8.48 (d, 1H, J=6.86 Hz, aryl H), 8.32 (d, 1H,J=9.10 Hz, aryl H), 8.10-8.09 (m, 3H, aryl H), 8.04-7.98 (m, 2H, arylH), 6.87 (d, 1H, J=9.36 Hz, aryl H), 6.59 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO-_(d6))

in ppm: 186.67 (C¹¹), 163.01 (C^(4a)), 161.01 (C^(4′), J=251.75 Hz),150.73 (C⁶), 149.67 (C³), 145.22 (C^(6a)), 141.37 (C^(2′), J=7.30 Hz),137.71 (C^(10a)), 133.77 (C¹), 132.56 (C^(1′)), 131.00 (C¹⁰), 124.19(C^(5′)), 123.66 (C⁷), 123.15 (C^(6′)), 122.70 (C⁹), 118.18 (C^(11a)),113.03 (C^(3′), J=23.44 Hz), 112.23 (C²), 105.28 (C⁴), 72.03 (C⁶)

IR (ATR) (cm⁻¹): 1585, 1531, 1516, 1308, 1264, 1246, 1138, 1036, 890,872, 815

MS (ESI) 408.3 [M−H]⁻

EXAMPLE 863-(2-Amino-4-fluorophenylamino)-8-nitro-6H-dibenzo[b,e]oxepin-11-one(12)

In accordance with general method Y, 0.60 g (2.66 mmol) of tin(II)chloride dihydrate is dissolved in 10 ml of ethanol, and 0.10 g (0.89mmol) of (11) is added. Yield: 0.01 g (11.9%);

melting point: 194.5° C.; C₂₀H₁₆FN₃O₂ (M_(r)=349.37); LC 7.34 min

¹H-NMR (MeOH-_(d4))

in ppm: 8.08 (d, 1H, J=8.97 Hz, aryl H), 7.77 (d, 1H, J=8.96 Hz, arylH), 7.07-6.96 (m, 1H, aryl H), 6.69-6.38 (m, 5H, aryl H), 6.07 (s, 1H,aryl H), 4.97 (s, 2H, —CH₂—O)

¹³C-NMR (MeOH-_(d4))

in ppm: 186.68 (C¹¹), 163.57 (C^(4a)), 155.84 (C^(4′), J=217.20 Hz),153.68 (C⁸), 149.21 (C³), 139.15 (C^(6a)), 133.41 (C¹), 131.81 (C¹⁰),130.23 (C^(1′)), 128.66 (C^(6′), J=11.6 Hz), 116.88 (C^(11a)), 115.34(C⁹), 113.61 (C⁷), 109.27 (C²), 105.34 (C^(5′), J=24.45 Hz), 103.03(C^(3′), J=23.18 Hz), 101.15 (C⁴), 73.67 (C⁶)

IR (ATR) (cm⁻¹): 1602, 1579, 1551, 1505, 1293, 1265, 1233, 1161, 1113,831, 759

MS (ESI) 350.5 [M+H]⁺

EXAMPLE 87 3-(2-Methoxyphenylamino)-8-nitro-6H-dibenzo[b,e]oxepin-11-one(14)

In accordance with general method Z, 0.80 g (2.96 mmol) of (6), 0.70 g(3.80 mmol) of 2-bromoanisole, 2 spatula tips of Pd(OAc)₂, 0.10 g of2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphineligand), 0.50 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out anddissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at100° C. under an argon atmosphere for 4 h. The crude product is purifiedby chromatography over silica gel with MC/EtOH (98/2). Yield: 0.025 g(2.2%); melting point: 200.3° C.

C₂₁H₁₆N₂O₆ (M_(r)=376.37); LC 9.03 min

¹H-NMR (DMSO-_(d6))

in ppm: 8.55 (s, 1H, aryl H), 8.47 (d, 1H, J=2.31 Hz, aryl H), 8.30 (dd,1H, J₁=2.47 Hz, J₂ ⁼2.41 Hz, aryl H), 8.02-7.92 (m, 2H, aryl H),7.27-7.23 (m, 1H, aryl H), 7.16-7.10 (m, 2H, aryl H), 6.99-6.95 (m, 1H,aryl H), 6.69 (dd, 1H, J₁=3.07 Hz, J₂ ⁼2.26 Hz, aryl H), 6.32 (d, 1H,J=2.19 Hz, aryl H), 5.32 (s, 2H, —CH₂—O), 3.78 (s, 3H, —O—CH₃)

¹³C-NMR (DMSO-_(d6))

in ppm: 185.73 (C¹¹), 163.30 (C^(4a)), 153.28 (C⁸), 152.84 (C^(2′)),149.43 (C³), 145.46 (C^(6a)), 137.82 (C^(10a)), 133.60 (C¹), 131.02(C¹⁰), 128.68 (C^(1′)), 125.78 (C⁹), 124.06 (C⁷), 123.51 (C^(5′)),121.00 (C^(4′)), 115.96 (C^(11a)), 112.60 (C^(3′)), 110.67 (C⁴), 71.98(—O—CH₂), 55.84 (—O—CH₃)

IR (ATR) (cm⁻¹): 3410, 1622, 1593, 1520, 1343, 1296, 1235, 1027, 768,761, 742

MS (ESI) 377.4 [M+H]⁺

EXAMPLE 88 8-Amino-3-(2-methoxyphenylamino)-6H-dibenzo[b,e]oxepin-11-one(15)

In accordance with general method Y, 0.10 g (0.44 mmol) of tin(II)chloride dihydrate is dissolved in 15 ml of ethanol, and 0.04 g (0.10mmol) of (14) is added. Yield: 0.0046 g (13.3%); melting point: 68.4°C.; C₂₁H₁₈N₂O₃ (M_(r)=346.39); LC 18.55 min

¹H-NMR (DMSO-_(d6))

in ppm: 8.52 (s, 1H, aryl H), 8.32 (d, 1H, J=5.19 Hz, aryl H), 7.98 (d,1H, J=6.31 Hz, aryl H), 7.85-7.24 (m, 4H, aryl H), 6.70-6.19 (m, 4H,aryl H), 5.95 (s, 2H, —NH₂), 4.96 (s, 2H, —CH₂—O), 3.78 (s, 3H, —OCH₃)

¹³C-NMR (DMSO-_(d6))

in ppm: 184.50 (C¹¹), 162.65 (C^(4a)), 153.38 (C⁸), 152.30 (C^(2′)),151.29 (C³), 139.20 (C^(6a)), 133.61 (C¹), 132.44 (C¹⁰), 129.51(C^(1′)), 127.17 (C^(10a)), 124.77 (C^(5′)), 122.91 (C^(6′)), 120.93(C^(4′)), 117.81 (C^(11a)), 113.47 (C^(3′)), 112.43 (C⁹), 111.66 (C⁷),110.19 (C²), 102.65 (C⁴), 74.34 (C⁶), 55.81 (—OCH₃)

MS (ESI) 347.3 [M+H]⁺

EXAMPLE 898-Nitro-3-(4-fluoro-2-methoxyphenylamino)-6H-dibenzo[b,e]oxepin-11-one(16)

In accordance with general method Z, 0.70 g (2.60 mmol) of (6), 0.55 g(2.68 mmol) of 2-bromo-5-fluoroanisole, 2 spatula tips of Pd(OAc)₂, 0.10g of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphineligand), 0.50 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out anddissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at100° C. under an argon atmosphere for 4 h. The crude product is purifiedby chromatography over silica gel with MC/EtOH (98/2). Yield: 0.07 g(0.01%); melting point: 222.3° C.

C₂₁H₁₅FN₂O₅ (M_(r)=394.36); LC 8.90 min

¹H-NMR (DMSO-_(d6))

in ppm: 8.64-8.27 (m, 3H, aryl H), 8.20-7.92 (m, 2H, aryl H), 7.24-7.01(m, 2H, aryl H), 6.87-6.58 (m, 2H, aryl H), 5.75 (s, 1H, —NH), 5.31 (s,2H, —CH₂—O), 3.94 (s, 3H, —OCH₃)

¹³C-NMR (DMSO-_(d6))

in ppm: 185.72 (C¹¹), 163.34 (C^(4a)), 160.42 (C^(4′), J=241.23 Hz),154.77 (C^(2′), J=10.51 Hz), 153.84 (C⁸), 149.40 (C³), 145.45 (C^(6a)),137.80 (C^(10a)), 133.66 (C¹), 131.01 (C¹⁰), 126.29 (C^(6′), J=10.16Hz), 124.81 (C^(1′), J=30.68 Hz), 124.01 (C⁷), 123.49 (C⁹), 115.80(C^(11a)), 110.29 (C²), 106.96 (C^(5′), J=22.03 Hz), 101.05 (C^(3′),J=26.81 Hz), not detected (C⁴), 71.98 (C⁶), 56.34 (—OCH₃)

IR (ATR) (cm⁻¹): 3314, 1613, 1552, 1510, 1307, 1279, 1235, 1151, 1189,957, 829, 816

MS (ESI) 395.3 [M+H]⁺

EXAMPLE 908-Amino-3-(4-fluoro-2-methoxyphenylamino)-6H-dibenzo[b,e]oxepin-11-one(17)

In accordance with general method Y, 0.30 g (1.32 mmol) of tin(II)chloride dihydrate is dissolved in 15 ml of ethanol, and 0.07 g (0.19mmol) of (16) is added. Yield: 0.042 g (60.6%); melting point: 38.9° C.;C₂₁H₁₇FN₂O₃ (M_(r)=364.38); LC 18.82 min

¹H-NMR (DMSO-_(d6))

in ppm: 8.17 (s, 1H, aryl H), 7.98 (d, 1H, J=14.89 Hz, aryl H), 7.64 (d,1H, J=11.40 Hz, aryl H), 7.27-7.19 (m, 1H, aryl H), 7.04-6.98 (m, 1H,aryl H), 6.81-6.72 (m, 1H, aryl H), 6.59-6.46 (m, 3H, aryl H), 6.05 (s,1H, —NH), 5.97 (s, 2H, —NH₂), 4.95 (s, 2H, —CH₂—O), 3.78 (s, 3H, —OCH₃)

¹³C-NMR (DMSO-_(d6))

in ppm: 184.49 (C¹¹), 162.70 (C^(4a)), 159.92 (C^(4′), J=240.08 Hz),154.35 (C^(2′), J=10.41 Hz), 153.37 (C⁸), 151.98 (C³), 139.18 (C^(6a)),133.67 (C¹), 132.43 (C¹⁰), 127.15 (C^(10a)), 125.59 (C^(6′), J=3.07 Hz),125.28 (C^(1′)), 117.58 (C^(11a)), 113.46 (C⁹), 111.65 (C⁷), 109.72(C²), 106.81 (C^(5′), J=21.98 Hz), 101.99 (C⁴), 100.92 (C^(3′), J=26.96Hz), 74.33 (C⁶), 56.29 (—OCH₃)

IR (ATR) (cm⁻¹): 3329, 2923, 1599, 1584, 1520, 1268, 1229, 1110, 1028,949, 832

MS (ESI) 365.2 [M+H]⁺

EXAMPLE 918-Nitro-3-(2-nitro-4-trifluoromethylphenylamino)-6H-dibenzo[b,e]oxepin-11-one(18)

In accordance with general method Z, 0.70 g (2.60 mmol) of (6), 0.55 g(3.05 mmol) of 4-chloro-3-nitro-benzotrifluoride, 2 spatula tips ofPd(OAc)₂, 0.10 g of2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (phosphineligand), 0.50 g of KOt-Bu, 2.0 ml of t-BuOH are weighed out anddissolved in 10 ml of toluene (anhydrous). The mixture is refluxed at100° C. under an argon atmosphere for 4 h. The crude product is purifiedby chromatography over silica gel with n-hexane/ethyl acetate (5/2).Yield: 0.047 g (3.9%);

melting point: 196.3° C.

C₂₁H₁₂F₃N₃O₆ (M_(r)=459.34); LC: 9.67 min

¹H-NMR (DMSO-_(d6))

in ppm: 9.74 (s, 1H, —NH), 8.54 (s, 1H, aryl H), 8.37-8.31 (m, 2H, arylH), 8.11-7.99 (m, 2H, aryl H), 7.90 (d, 1H, J=9.30 Hz, aryl H), 7.13 (d,1H, J=8.08 Hz, aryl H), 6.98 (s, 1H, aryl H), 5.45 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO-_(d6))

in ppm: 187.42 (C¹¹), 162.55 (C^(4a)), 149.84 (C⁸), 147.66 (C³), 145.08(C^(1′)), 141.09 (C^(6a)), 137.64 (C^(2′)), 136.89 (C^(10a)), 133.52(C^(5′)), 131.72 (C¹⁰), 130.98 (C¹), 124.32 (C⁹), 123.77 (C⁷), 121.73(CF₃), 121.33 (C^(3′)), 120.65 (C^(4′)), 120.32 (C^(6′)), 120.00(C^(11a)), 115.32 (C²), 110.32 (C⁴), 72.04 (C⁶)

IR (ATR) (cm⁻¹): 3324, 1636, 1603, 1574, 1531, 1324, 1150, 1112, 1083,914, 819, 709

MS (ESI) 458.6 [M−H]⁻

EXAMPLE 928-Amino-3-(2-amino-4-trifluoromethylphenylamino)-6H-dibenzo[b,e]oxepin-11-one(19)

In accordance with general method Y, 0.30 g (1.32 mmol) of tin(II)chloride dihydrate is dissolved in 15 ml of ethanol, and 0.095 g (0.20mmol) of (18) is added. Yield: 0.061 g (76.4%); melting point: 93.9° C.;C₂₁H₁₆F₃N₃O₂ (M_(r)=399.38); LC 19.06 min

¹H-NMR (DMSO-_(d6))

in ppm: 8.14 (s, 1H, aryl H), 8.00 (d, 1H, J=8.90 Hz, aryl H), 7.65 (d,1H, J=8.53 Hz, aryl H), 7.20 (d, 1H, J=8.12 Hz, aryl H), 7.06 (s, 1H,aryl H), 6.85 (d, 1H, J=8.57 Hz, aryl H), 6.62-6.55 (m, 2H, aryl H),6.45 (s, 1H, aryl H), 6.23 (d, 1H, J=2.04 Hz, aryl H), 6.05 (s, 2H,—NH₂), 5.31 (s, 2H, —NH₂), 4.96 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO-_(d6))

in ppm: 184.61 (C¹¹), 162.66 (C^(4a)), 153.44 (C⁸), 151.07 (C³), 143.35(C^(1′)), not detected (C^(6a)) 139.20 (C^(2′)), 133.79 (C¹), 132.47(C¹⁰), 129.17 (CF₃), 127.06 (C^(4′)), 125.45 (C^(5′)), 124.47 (C^(6′)),118.09 (C^(11a)), 113.50 (C9), 113.01 (C^(3′)), 111.70 (C⁷), 110.33(C²), 102.90 (C⁴), 74.39 (C⁶)

IR (ATR) (cm⁻¹): 3352, 1599, 1521, 1334, 1293, 1231, 1160, 1116, 917,815 MS 400.3 [M+H]⁺

EXAMPLE 93 3-(Tetrazol-1-yl)-8-nitro-6H-dibenzo[b,e]oxepin-11-one (20)

0.50 g (1.85 mmol) of (6) and 0.35 g (5.38 mmol) of sodium azide aresuspended in 2.20 g (14.84 mmol) of trimethyl orthoformate at 0° C. 1.20g (20.00 mmol) of glacial acetic acid are then added to the mixture andthe mixture is heated to 100° C. and refluxed for 4 h. After cooling toroom temperature, the mixture is concentrated in vacuo and the residueis taken up with EtOAc and dissolved under the influence of heat. Thewhite-grey product precipitates out in the cold. Yield: 0.50 g (83.6%);melting point: 123-126° C.; C₁₅H₉N₅O₄ (M_(r)=323.27)

¹H-NMR (DMSO-_(d6))

in ppm: 10.27 (s, 1H, tetrazole), 8.59 (s, 1H, aryl H), 8.39-8.30 (m,2H, aryl H), 8.03 (d, 1H, J=8.62, aryl H), 7.85-7.80 (m, 2H, aryl H),5.60 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO)

in ppm: 188.40 (C¹¹), 161.95 (C^(4a)), 150.21 (C⁸), 144.68 (tetrazole),137.54 (C^(10a)), 133.19 (C¹⁰), 131.19 (C¹), 125.02 (C⁷), 124.55 (C²),124.00 (C^(11a)), 114.81 (C⁹), 112.81 (C⁴), 70.01 (C⁶)

EXAMPLE 94 8-Amino-3-(tetrazol-1-yl)-6H-dibenzo[b,e]oxepin-11-one (21)

In accordance with general method Y, 1.50 g (6.66 mmol) of tin(II)chloride dihydrate are dissolved in 10 ml of ethanol, and 0.50 g (1.54mmol) of (20) is added.

Yield: 0.027 g (6.1%); melting point: 277.0° C.; C₁₅H₁₁N₅O₂(M_(r)=293.29)

¹H-NMR (DMSO-d6)

in ppm: 10.21 (s, 1H, tetrazole), 8.39 (d, 1H, J=8.58 Hz, aryl H), 7.73(d, 3H, J=9.92 Hz, aryl H), 6.64-6.54 (m, 2H, aryl H), 6.34 (s, 2H,—NH₂), 5.18 (s, 2H, —CH₂—O)

¹³C-NMR (DMSO)

in ppm: 184.72 (C¹¹), 161.51 (C^(4a)), 154.61 (C⁸), 142.78 (C^(6a)),139.50 (C³), 137.80 (tetrazole), 134.41 (C¹⁰), 133.14 (C¹), 127.30 (C²),126.05 (C^(10a)), 114.65 (C^(11a)), 113.78 (C⁹), 112.69 (C⁷), 111.90(C⁴), 74.99 (C⁶)

IR (ATR) (cm⁻¹): 1608, 1588, 1553, 1501, 1374, 1300, 1196, 1002, 842,762, 700

EXAMPLE 953-(2,4-Difluorophenylamino)-8-tetrazol-1-yl-6H-dibenzo[b,e]oxepin-11-one(13)

0.015 g (0.042 mmol) of (8) and 0.01 g (0.15 mmol) of sodium azide aresuspended in 0.05 g (0.33 mmol) of trimethyl orthoformate at 0° C. 0.03g (0.50 mmol) of glacial acetic acid is then added to the mixture andthe mixture is heated to 100° C. and refluxed for 4 h. After cooling toroom temperature, the mixture is concentrated in vacuo and the residueis taken up with EtOAc and dissolved under the influence of heat. Theyellow product precipitates out in the cold.

Yield: 0.26 g (88.1%); melting point: 59.0° C.

C₂₁H₁₃F₂N₅O₂ (M_(r)=405.37); LC 8.15 min

¹H-NMR (DMSO-_(d6))

in ppm: 10.21 (s, 1H, tetrazole), 9.02 (s, 1H, —NH), 8.18 (s, 1H, arylH), 8.10-7.98 (m, 3H, aryl H), 7.48-7.39 (m, 2H, aryl H), 7.38-7.32 (m,1H, aryl H), 6.65 (d, 1H, J=9.84 Hz, aryl H), 6.26 (s, 1H, aryl H), 5.34(s, 2H, —CH₂—O)

¹³C-NMR (DMSO-_(d6))

in ppm: 174.70 (C¹¹), 163.21 (C^(4a)), not detected (C4′), 155.34(C^(2′), J=267.55 Hz), 142.79 (C³), 140.74 (tetrazole), 138.38 (C^(6a)),136.36 (C¹), 133.85 (C⁸), 131.53 (C^(10+10a)), not detected (C⁹), 121.42(C^(6′)), 120.00 (C^(1′)), 116.75 (C^(5′)), 110.28 (C²), 102.02 (C⁴),72.60 (C⁶)

IR (ATR) (cm⁻¹): 2790, 2565, 1644, 1608, 1531, 1297, 1250, 1150, 1085,907, 819, 708 MS (ESI) 404.1 [M−H]⁻

EXAMPLE 96 2-(2-Methyl-4-Fluoroanilino)-7-methoxydibenzosuberone (10m)

For the preparation of compound 10m, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.25 g (2.0 mmol) of3-methyl-4-fluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21mmol) of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-biphenyl, 0.70g (6.2 mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used andare reacted by method C.

H₁-NMR (DMSO-d6) δ in ppm: 2.96 (s, 4H, —CH₂—CH₂—), 3.76 (s, 3H, —OCH₃),6.46 (s, 1H, C¹—H), 6.61 (d, 1H, J=8.8, C³—H), 6.99-7.26 (m, 5H, C⁸—H,C⁹—H,

—H,

—H, C⁵—H), 7.38 (s, 1H, C⁶—H), 7.94 (s, d, 1H, J=8.7, C⁴—H), 8.22 (s,1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.5 (C¹²), 36.4 (C¹¹), 55.5 (—OCH₃), 111.9(C⁶), 113.1 (C³), 113.7 (d, 1C, J=22.2,

), 114.7 (C¹), 117.7 (d, 1C, J=22.0,

), 118.4 (C³), 126.7 (C⁸), 127.0 (

), 130.4 (C⁹), 134.0 (C^(5a)), 134.5 (C⁴), 135.4 (d, 1C, J=2.6,

), 136.2 (d, 1C, J=8.3,

—H), 140.2 (C^(9a)), 145.9 (C^(11a)), 150.9 (C²), 158.0 (C⁷), 159.6 (d,1C, J=241.0,

), 190.5 (C⁵).

EXAMPLE 97 2-(2-Chloroanilino)-7-methoxydibenzosuberone (10n)

For the preparation of compound 10n, 0.5 g (1.8 mmol) of2-chloro-7-methoxydibenzosuberone, 0.27 g (2.1 mmol) of 2-chloroaniline,0.05 g (0.22 mmol) of Pd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used and arereacted by method C.

H₁-NMR (DMSO-d6) δ in ppm: 3.00 (s, 4H, —CH₂—CH₂—), 3.77 (s, 3H, —OCH₃),6.73 (s, 1H, C¹—H), 6.84 (d, 1H, C³—H), 7.02-7.54 (m, 7H, C⁶—H, C⁷—H,C⁸—H,

—H,

—H,

—H,

), 7.95 (d, 1H, J=8.7, C⁴—H), 8.45 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 33.5 (C¹²), 36.2 (C¹¹), 55.5 (—OCH₃), 113.4(C⁶), 114.6 (C³), 114.9 (C¹), 118.6 (C⁸), 124.5 (

), 125.4 (

), 127.3 (

), 128.1 (C^(4a)), 128.4 (

), 130.6 (C⁹), 130.7 (

), 133.7 (C⁴), 134.5 (C^(5a)), 138.1 (

), 140.0 (C^(9a)), 145.6 (C^(11a)), 148.9 (C²), 158.1 (C⁷), 190.9 (C⁵).

EXAMPLE 982-(2,4-Difluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(11a)

0.2 g (0.55 mmol) of2-(2,4-difluoroanilino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-oneis dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are addedand the mixture is refluxed for 6 h. The solution is hydrolyzed with 200g of ice and the precipitate is filtered off. The product is obtained inthe form of a white powder. C₂₁H₁₅F₂NO₂ (Mr=351.35)

EXAMPLE 992-(2-Amino-4-fluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(11b)

0.2 g (0.55 mmol) of2-(2-amino-4-fluoroanilino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-oneis dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are addedand the mixture is refluxed for 6 h. The solution is hydrolyzed with 200g of ice and the precipitate is filtered off. The product is obtained inthe form of a white powder. C₂₁H₁₇FN₂O₂ (Mr=348.38)

EXAMPLE 1002-(2-Chloro-4-fluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(11c)

C₂₁H₁₅ClFNO₂ (Mr=367.81)

0.2 g (0.52 mmol) of2-(2-chloro-4-fluoroanilino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-oneis dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are addedand the mixture is refluxed for 6 h. The solution is hydrolyzed with 200g of ice and the precipitate is filtered off. The product is obtained inthe form of a white powder.

EXAMPLE 1012-(2-Chloroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(11d)

0.2 g (0.55 mmol) of2-(2-chloroanilino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-oneis dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are addedand the mixture is refluxed for 6 h. The solution is hydrolyzed with 200g of ice and the precipitate is filtered off. The product is obtained inthe form of a white powder.

EXAMPLE 1022-(Anilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (11e)

0.2 g (0.61 mmol) of2-anilino-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one isdissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are addedand the mixture is refluxed for 6 h. The solution is hydrolyzed with 200g of ice and the precipitate is filtered off. The product is obtained inthe form of a white powder. C₂₁H₁₇NO₂ (Mr=315.380)

EXAMPLE 1032-(2,4-Difluoroanilino)-7-hydroxy-dibenzo[a,d]-cyclohepten-5-one

0.2 g (0.55 mmol) of2-(2-amino-4-fluoroanilino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-oneis dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are addedand the mixture is refluxed for 6 h. The solution is hydrolyzed with 200g of ice and the precipitate is filtered off. The product is obtained inthe form of a white powder.

EXAMPLE 1042-(2,4-Difluoroanilino)-7-[3-(4-hydroxypiperidin-4-yl-propoxy)]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14n)

For the preparation of compound 14, 0.72 g (1.8 mmol) of2-chloro-7-[3-(4-hydroxypiperidin-4-yl-propoxy)]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one,0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used.

EXAMPLE 1053-(2-Amino-4-fluorophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one(58)

0.60 g (2.66 mmol) of tin(II) chloride dihydrate is dissolved in 10 mlof EtOH, 0.10 g (0.89 mmol) of the 8-nitro compound is added and thereaction is carried out by method D.

Yield: 0.01 g (11.9%); melting point: 194.5° C.; C₂₀H₁₆FN₃O₂(M_(r)=349.37); LC 7.34 min

¹H-NMR (MeOH-d₄) δ in ppm: 8.08 (d, 1H, J=8.97 Hz, aryl H), 7.77 (d, 1H,J=8.96 Hz, aryl H), 7.07-6.96 (m, 1H, aryl H), 6.69-6.38 (m, 5H, arylH), 6.07 (s, 1H, aryl H), 4.97 (s, 2H, —CH₂—O)

¹³C-NMR (MeOH-d₄) δ in ppm: 186.68 (C¹¹), 163.57 (C^(4a)), 155.84(C^(4′), J=217.20 Hz), 153.68 (C⁸), 149.21 (C³), 139.15 (C^(6a)), 133.41(C¹), 131.81 (C¹⁰), 130.23 (C^(1′)), 128.66 (C^(6′), J=11.6 Hz), 116.88(C^(11a)), 115.34 (C⁹), 113.61 (C⁷), 109.27 (C²), 105.34 (C^(5′),J=24.45 Hz), 103.03 (C^(3′), J=23.18 Hz), 101.15 (C⁴), 73.67 (C⁶)

IR (ATR) (cm⁻¹): 1602, 1579, 1551, 1505, 1293, 1265, 1233, 1161, 1113,831, 759

MS (ESI) 350.3 [M+H]⁺

EXAMPLE 106 Morpholine-4-carboxylic acid[3-(2,4-difluorophenylamino)-1-oxo-6,11-dihydrodibenzo[b,e]oxepin-8-yl]amide

0.025 g (0.16 mmol) of morpholine-4-carboxylic acid chloride is slowlyadded dropwise to a solution of 0.05 g (0.14 mmol) of3-(2,4-difluorophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one and0.03 g (0.30 mmol) of triethylamine (freshly distilled) in 3 ml oftetrahydrofuran, while cooling with ice. When the addition has ended,the mixture is stirred at RT under an argon atmosphere for 2 h. At theend of the reaction, excess solvent is evaporated off on a rotaryevaporator, the residue is taken up in EtOAc and the mixture isextracted by shaking against 5% strength NaHCO₃ solution. The organicphase is evaporated on a rotary evaporator, the crude product isrecrystallized in MeOH/H₂O and the product is then washed with diethylether and dried.

Yield: 0.03 g (46.0%); melting point: 244.3° C.; C₂₅H₂₁F₂N₃O₄(M_(r)=465.46); LC 7.76 min

¹H-NMR (DMSO-d₆)

in ppm: 7.99 (d, 1H, J=8.69 Hz, aryl H), 7.70 (d, 1H, J=2.83 Hz, arylH), 7.39-7.34 (m, 2H, aryl H), 7.12-7.08 (m, 1H, aryl H), 6.70-6.57 (m,3H, aryl H), 6.24 (s, 1H, aryl H), 5.05 (s, 2H, —CH₂—O)

IR (ATR) (cm⁻¹): 1556, 1512, 1309, 1229, 1097, 911, 872, 833, 694

MS (ESI) 464.1 [M−H]⁻

General Method AA

For the preparation of the test compounds, a mixture of aryl halide,aniline derivative, Pd(OAc)₂, phosphine ligand, Na—O-tert-butylate orK-O-tert-butylate, toluene and tert-BuOH is heated to 100° C. under anargon inert gas atmosphere and stirred at this temperature for thestated time. Thereafter, the mixture is cooled to room temperature,hydrolysis is carried out with 150 ml of H₂O, the mixture is extracted3× with 200 ml of diethyl ether each time and the organic phase isfiltered and concentrated in vacuo. Purification is carried out viaflash chromatography.

General Method AB

For hydrolysis of the acetal in MeOH, the stated amount of H₂O andp-toluenesulfonic acid is added. The solution is heated to 50° C. underan argon inert gas atmosphere. After 6 h, the solution is cooled to roomtemperature and concentrated in vacuo. A yellow oil is obtained, whichis dissolved again in ethyl acetate and 5% strength Na₂HCO₃ solution (50ml). The organic phase is separated off and concentrated in vacuo. Thediol precipitates out in the form of a white solid, which isrecrystallized from methylene chloride/hexane.

General Method AC

For the preparation of the secondary amine, the stated amounts of theamino component are dissolved in a toluene/tert-butanol mixture in a dry100 ml three-necked flask with a reflux condenser and bubble counterunder an argon atmosphere, with heating. The stated amounts of thephosphine ligand(2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl,K-O-tert-butylate, halogen component and Pd(OAc)₂ are now added and themixture is refluxed at 110° C. under an argon atmosphere for 2-6 h underTLC monitoring. When the reaction has ended, the mixture is cooled to RTand filtered. The residue on the filter is washed several times withmethylene chloride, methanol and ethyl acetate and the combined organicphases are concentrated in vacuo. The brown product mixture whichthereby remains is purified by chromatography with hexane:ethyl acetate(3:1) over silica gel.

EXAMPLE 1072-(2,4-Difluorophenylamino)-7-(3-morpholin-4-yl-propoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(55k)

In accordance with general method AA, 0.67 g (1.8 mmol) of2-chloro-7-(3-morpholin-4-yl-propoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(36i), 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH areused. Reaction time: 1 h. Purification is carried out via flashchromatography (SiO₂, hexane/ethyl acetate 7+3). C₂₈H₂₈F₂N₂O₃(Mr=478.54); yield 43%; m.p. 114° C.

IR (ATR)* 3313 (N—H), 2852, 1567, 1527, 1496, 1270, 1196, 1146, 1116,1093, 961, 863, 816 cm⁻¹

¹H-NMR (DMSO-d6) δ in ppm: 1.79-1.92 (m, 2H, C2propoxy-H), 2.34-2.43 (m,6H, C3/5-morpholinyl-H, C3propoxy-H), 2.99 (s, 4H, —CH2-CH2-), 3.55 (t,4H, J=3.6 Hz, C2/6-morpholinyl-H), 4.01 (t, 2H, J=5.8 Hz, C1propoxy-H);6.60 (s, 1H, C1-H), 6.73 (d, 1H, J=8.7 Hz, C3-H), 7.00-7.38 (m, 6H,C6-H, C8-H, C9-H, C3′-H, C5′-H, C6′-H), 7.94 (d, 1H, J=8.6 Hz, C4-H),8.53 (s, 1H, —NH—)

¹³C-NMR (DMSO-d6) δ in ppm: 26.2 (C2propoxy), 33.5 (C10), 36.2 (C11),53.7 (2C, C3/5-morpholinyl), 55.1 (C3propoxy), 65.3 (C1propoxy), 66.5(2C, C2/6-morpholinyl), 105.3 (dd, 1C, J1=24.1 Hz, J2=26.8 Hz, C3′),112.2 (dd, 1C, J1=3.8 Hz, J2=22.4 Hz, C5′), 112.6 (C6), 113.8 (C3),115.2 (C1), 119.2 (C8), 125.2 (dd, 1C, J1=4.2 Hz, J2=11.9 Hz, C1′),126.4 (dd, 1C, J1=3.4 Hz, J2=9.8 Hz, C6′), 127.7 (C4a), 130.6 (C9),133.8 (C5a), 134.5 (C4), 140.0 (C9a), 145.7 (C11a), 149.4 (C2), 156.0(dd, 1C, J1=12.7 Hz, J2=248.3 Hz, C4′), 158.3 (C7), 158.8 (dd, 1C,J1=12.2 Hz, J2=242.2 Hz, C2′), 190.8 (C5)

EXAMPLE 1082-(2,4-Difluorophenylamino)-8-(3-hydroxypropoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(12j)

In accordance with general method O, 0.65 g (1.8 mmol) of acetic acid3-(8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-propylester, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)₂,0.17 g of phosphine ligand and 0.74 g (7.7 mmol) of Na—O-tert-butylateare reacted in 10 ml of toluene and 2 ml of tert-BuOH. Yield: 42%; m.p.:154° C.

C₂₄H₂₁F₂NO₃ (Mr=409.44); HPLC 8.7 min; 98.3%

IR (ATR) (cm⁻¹): 3359, 2918, 1605, 1581, 1529, 1270, 1240, 1118, 1098,1055, 960, 843, 772, 692, 455.

¹H-NMR (DMSO-d6) δ in ppm: 1.86 (q, 2H, J=6.28 Hz, C2-Hhydroxy-propoxy), 3.01 (dd, 4H, J1=12.45 Hz, J2=9.23 Hz, —CH2-CH2-),3.55 (dd, 2H, J1=11.44 Hz, J2=5.97 Hz, C3-H hydroxypropoxy), 4.11 (t,2H, J=6.30 Hz, C1-H hydroxypropoxy), 4.56 (t, 1H, J=5.11 Hz, —OH), 6.61(s, 1H, C1-H), 6.73 (d, 1H, J=8.90 Hz, C3-H), 6.84-6.91 (m, 2H,C3′—/C6′-H), 7.03-7.14 (m, 1H, C5′-H), 7.29-7.42 (m, 2H, C7-/C9-H), 7.96(d, 2H, J=8.71 Hz, C4-/C6-H), 8.49 (s, 1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 32.4 (C2 hydroxypropoxy), 35.2 (C11), 35.8(C10), 57.5 (C3 hydroxypropoxy), 65.2 (C1 hydroxypropoxy), 105.3 (dd,J1=26.6 Hz, J2=23.9 Hz, C3′), 112.1 (dd, J1=26.6 Hz, J2=23.9 Hz, C5′),112.5 (C7), 113.0 (C9), 113.6 (C3), 114.4 (C1), 125.4 (dd, J1=12.0 Hz,J2=3.6 Hz, C1′), 126.2 (dd, J1=9.6 Hz, J2=3.3 Hz, C6′), 128.3 (C4a),131.2 (C5a), 133.7 (C6), 133.8 (C4), 145.2 (C9a), 145.3 (C2), 149.1(C11a), 155.9 (dd, J1=246.3 Hz, J2=12.4 Hz, C4′), 158.6 (dd, J1=234.8Hz, J2=11.8 Hz, C2′), 161.9 (C8), 189.1 (C5).

EXAMPLE 1092-(2,4-Difluorophenylamino)-8-(2-hydroxyethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(12k)

In accordance with general method O, 0.67 g (0.19 mmol) of acetic acid2-(8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-ethylester, 0.26 g (0.0020 mol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)₂,0.14 g of phosphine ligand and 0.70 g (7.3 mmol) of Na-β-tert-butylateare reacted in 10 ml of toluene and 2 ml of tert-BuOH. Yield: 20%; m.p.:138° C.

C₂₃H₁₉F₂NO₃ (Mr=395.41); HPLC 8.1 min; 98.1%

IR (ATR) (cm⁻¹): 3406, 3283, 2919, 1596, 1535, 1495, 1343, 1297, 1265,1239, 1210, 1186, 1108, 1093, 1077, 1042, 959, 857, 847, 781, 655, 497,455.

¹H-NMR (DMSO-d6) δ in ppm: 2.97-3.07 (m, 4H, —CH2-CH2-), 3.68-3.76 (m,2H, C2-H hydroxyethoxy), 4.06 (t, 2H, J=4.78 Hz, C1-H hydroxyethoxy),4.89 (t, 1H, J=5.48 Hz, —OH), 6.61 (s, 1H, C1-H), 6.73 (d, 1H, J=8.53Hz, C3), 6.85-6.92 (m, 2H, C3′-/C6′-H), 7.05-7.13 (m, 1H, C5′-H),7.29-7.43 (m, 2H, J=8.71 Hz, C4-/C6-H), 8.47 (s, 1H, —NH—).

EXAMPLE 1102-(2,4-Difluorophenylamino)-8-methoxy-10,11-dihydrodibenzo[a,d]cyclo-hepten-5-one(12a)

In accordance with general method O, 0.52 g (1.9 mmol) of2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.30 g(2.3 mmol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)₂, 0.16 g ofphosphine ligand and 0.86 g (8.9 mmol) of Na—O-tert-butylate are reactedin 10 ml of toluene and 2 ml of tert-BuOH. Purification is carried outby column chromatography (flash; SiO₂; hexane 90%/ethyl acetate 10%).Yield: 66%; m.p.: 157° C.

C₂₂H₁₇F₂NO₂ (Mr=365.38); HPLC 9.4 min, 99.9%; GC 34.6 min

MS m/z (%): 365 (100, M+), 350 (3, M+-CH3), 337 (5, M+-CO), 322 (14,337-CH3), 208 (10, 350-O, -difluoroaniline), 194 (3, 322-O,-difluorobenzene), 178 (3, 322-OH, -difluoroaniline), 165 (14,4-methoxy-2-methylbenzoic acid), 152 (4, 165-CH2).

IR (ATR) (cm⁻¹): 3302, 2913, 1581, 1494, 1261, 1238, 1138, 1093, 1033,965, 954, 862, 846, 777, 729, 695, 563, 511, 444.

¹H-NMR (DMSO-d6) δ in ppm: 3.02 (dd, 4H, J1=13.73 Hz, J2=8.96 Hz,—CH2-CH2-), 3.82 (s, 3H, —OCH3), 6.61 (s, 1H, C1-H), 6.73 (d, 1H, J=8.64Hz, C3-H), 6.84-6.92 (m, 2H, C3′-C6′-H), 7.04-7.13 (m, 1H, C5′-H),7.34-7.42 (m, 2H, C7-/C9-H), 7.96 (d, 2H, J=8.64 Hz, C4-/C6-H), 8.49 (s,1H, —NH—).

¹³C-NMR (DMSO-d6) δ in ppm: 35.2 (C11), 35.8 (C10), 55.7 (—OCH3), 105.3(dd, J1=26.5 Hz, J2=24.0 Hz, C3′), 112.1 (dd, J1=21.5 Hz, J2=3.7 Hz,C5′), 112.5 (C7), 112.7 (C9), 113.6 (C3), 113.9 (C1), 125.4 (dd, J1=12.1Hz, J2=3.6 Hz, C1′), 126.3 (dd, J1=9.1 Hz, J2=3.3 Hz, C6′), 128.2 (C4a),131.3 (C5a), 133.7 (C4), 133.8 (C6), 145.1 (C2), 145.3 (C11a), 149.1(C9a), 155.9 (dd, J1=246.4 Hz, J2=12.5 Hz, C4′), 158.7 (dd, J1=241.6 Hz,J2=11.4 Hz, C2′), 162.4 (C8′), 189.1 (C5).

EXAMPLE 1112-(2-Aminophenylamino)-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(12b)

In accordance with general method O, 0.48 g (1.8 mmol) of2-chloro-8-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 1.05 g(9.7 mmol) of phenylenediamine, 0.04 g of Pd(OAc)₂, 0.20 g of phosphineligand and 1.65 g (17 mmol) of Na—O-tert-butylate are reacted in 10 mlof toluene and 2 ml of tert-BuOH. Purification is carried out by columnchromatography (flash; SiO₂; hexane 80%/ethyl acetate 20%). Yield: 35%;m.p.: 200° C.

C₂₂H₂₀N₂O₂ (Mr=344.42); HPLC 8.2 min; 99.6%; GC 63.6 min

MS m/z (%): 344 (100, M+), 329 (8, M+-CH3), 315 (5, M^(+-CO),) 301 (9,315-CH3), 195 (10, 315-O, -aminobenzene), 158 (11), 107 (7,diaminobenzene).

IR (ATR) (cm⁻¹): 311, 2921, 2852, 1287, 1262, 1240, 1206, 1153, 1092,1031, 835, 744, 696, 595, 562, 489, 441.

¹H-NMR (DMSO-d6) δ in ppm: 2.98 (dd, 4H, J1=17.6 Hz, J2=8.96 Hz,—CH2-CH2-), 3.81 (s, 3H, —OCH3), 4.84 (s, 2H, —NH2), 6.47 (s, 1H, C1-H),6.57-6.64 (m, 2H, C3′-/C6′-H), 6.76-6.91 (m, 5H, C3-/C7-/C9-H andC4′-/C5′-H), 7.91-7.98 (m, 3H, —NH— and C4-/C6-H).

¹³C-NMR (DMSO-d6) δ in ppm: 35.2 (C11), 36.1 (C10), 55.7 (—OCH3), 112.0(C7), 112.6 (C9), 112.8 (C3), 113.8 (C1), 115.8 (C3′), 116.8 (C4′),125.4 (C4a), 126.1 (C6′), 126.3 (C5′), 126.7 (C5a), 131.6 (C1), 133.7(C4), 133.9 (C6), 144.0 (C2′), 145.0 (C2), 145.4 (C11a), 150.8 (C9a),162.2 (C8), 188.7 (C5).

EXAMPLE 1122-(2,4-Difluoro-phenylamino)-7-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(55h)

In accordance with general method AA, 0.70 g (1.8 mmol) of2-chloro-7-(2((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(360, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2 mmol) of Na—O-tert-butylate, 5ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h.Purification is carried out via flash chromatography (SiO₂, hexane/ethylacetate 7+3). Yield: 45%;

m.p.: 123° C.

C₂₈H₂₇F₂NO₄ (Mr=479.53)

IR (ATR)* 3307 (N—H), 1607, 1552, 1499, 1355, 1286, 1201, 1142, 1093,1054, 962, 869, 786 cm⁻¹

¹H-NMR (DMSO-d6) δ in ppm: 1.25 (s, 3H, —CH3), 1.31 (s, 3H, —CH3),1.89-1.98 (m, 2H, C2ethoxy-H), 2.99 (s, 4H, —CH2-CH2-), 3.52-3.59 (m,1H, C5-dioxolanyl-H), 4.00-4.23 (m, 4H, C1ethoxy-H, C4-dioxolonyl-H,C5-dioxolanyl-H), 6.60 (s, 1H, C1-H), 6.73 (d, 1H, J=8.7 Hz, C3-H);7.00-7.46 (m, 6H, C6-H, C8-H, C9-H, C3′-H, C5′-H, C6′-H), 7.94 (d, 1H,J=8.8 Hz, C4-H), 8.54 (s, 1H, —NH—)

¹³C-NMR (DMSO-d6) δ in ppm: 26.0 (—CH3), 27.2 (—CH3), 33.3 (C2ethoxy),33.5 (C10), 36.2 (C11), 65.0 (C1ethoxy), 69.0 (C5-dioxolanyl), 73.2(C4-dioxolanyl), 105.3 (dd, 1C, J1=24.5 Hz, J2=26.7 Hz, C3′), 108.3(C2-dioxolanyl), 112.2 (dd, 1C, J1=3.8 Hz, J2=22.2 Hz), 112.6 (C6),113.8 (C3), 115.3 (C1), 119.0 (C8), 125.3 (dd, 1C, J1=3.8 Hz, J2=12.0Hz, C1′), 126.4 (dd, 1C, J1=3.5 Hz, J2=9.8 Hz, C6′), 127.7 (C4a), 130.6(C9), 133.8 (C5a), 134.7 (C4), 140.0 (C9a), 145.7 (C11a), 149.5 (C2),156.0 (dd, 1C, J1=12.3 Hz, J2=248.0 Hz, C4′), 158.6 (C7); 158.8 (dd, 1C,J1=11.5 Hz, J2=242.9 Hz, C2′), 190.8 (C5)

EXAMPLE 1132-(2,4-Difluorophenylamino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclo-hepten-5-one(52b)

In accordance with general method AA, 0.50 g (1.8 mmol) of2-chloro-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (34),0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2mmol) of K-O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH areused. Reaction time: 1 h. Purification is carried out via flashchromatography (SiO₂, hexane/ethyl acetate 8+2). Yield: 87%; meltingpoint: 123-126° C. (decomposition)

C₂₂H₁₇F₂NO₂ (Mr=365.38); GC 31.4 min

MS m/z (%): 365 (100, M+), 350 (7, M⁺-CH₃), 337 (11), 322 (6), 237 (4,M⁺-2-(NH₂—, 4-F-aniline)), 208 (15), 194 (5), 178 (6), 165 (15), 152 (5)

IR (ATR) 3327 (N—H), 3074 (C—H), 2941-2842 (C—H), 1604, 1552, 1525,1498, 1338, 1325, 1281, 1238, 854, 832, 786 cm⁻¹

¹H-NMR (DMSO-d6) δ in ppm: 2.99 (s, 4H, —CH2-CH2-), 3.76 (s, 3H, —OCH3),6.61 (s, 1H, C1-H), 6.74 (d, 1H, J=8.7 Hz, C3-H), 7.00-7.47 (m, 6H,C6-H, C8-H, C9-H, C3′-H, C5′-H, C6′-H), 7.95 (d, 1H, J=8.8 Hz, C4-H),8.55 (s, 1H, —NH—)

¹³C-NMR (DMSO-d6) δ in ppm: 33.5 (C10), 36.2 (C11), 55.5 (—OCH3), 105.3(dd, 1C, J1=24.3 Hz, J2=26.7 Hz, C3′), 112.2 (dd, 1C, J1=3.5 Hz, J2=21.8Hz, C5′), 112.6 (C6), 113.9 (C3), 114.7 (C1), 118.6 (C8), 125.3 (dd, 1C,J1=3.8 Hz, J2=12.3 Hz, C1′), 126.4 (dd, 1C, J1=3.4 Hz, J2=9.6 Hz, C6′),127.7 (C4a), 130.6 (C9), 133.8 (C5a), 134.6 (C4), 140.0 (C9a), 145.7(C11a), 149.4 (C2), 156.0 (dd, 1C, J1=12.3 Hz, J2=248.1 Hz, C4′), 158.1(C7), 158.8 (dd, 1C, J1=11.1 Hz, J2=143.1 Hz, C2′), 190.8 (C5)

EXAMPLE 1147-Methoxy-2-(2,3,4-trifluorophenylamino)-10,11-dihydrodibenzo[a,d]-cyclo-hepten-5-one(52n)

In accordance with general method AA, 0.50 g (1.8 mmol) of2-chloro-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (34),0.27 g (1.8 mmol) of 2,3,4-trifluoroaniline, 0.05 g (0.22 mmol) ofPd(OAc)₂, 0.10 g (0.21 mmol) of2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH areused. Reaction time: 1 h. Purification is carried out via flashchromatography (SiO₂, hexane/ethyl acetate 8+2). Yield: 72%; meltingpoint: 128° C.

C₂₂H₁₆F₃NO₂ (Mr=383.37); GC 32.0 min

MS m/z (%): 383 (100, M⁺), 368 (7, M⁺-CH₃), 355 (10), 340 (5), 237 (3),208 (11), 194 (5), 178 (6), 165 (11)

IR (ATR)* 2930, 1578, 1492, 1355, 1265, 1035, 1000, 970, 839, 814 cm⁻¹

¹H-NMR (DMSO-d6) δ in ppm: 3.03 (s, 4H, —CH2-CH2-), 3.77 (s, 3H, —OCH),6.95-7.47 (m, 7H, C1-H, C3-H, C6-H, C8-H, C9-H, C5′-H, C6′-H), 7.92 (d,1H, J=8.6 Hz, C4-H), N—H-signal not visible.

¹³C-NMR (DMSO-d6) δ in ppm: 33.3 (C10), 35.2 (C11), 55.6 (—OCH3),113.6-114.0 (m, 1C, C1′); 114.3 (C6); 119.2 (C3), 119.8 (C1), 122.0(C8), 125.0-125.2 (m, 1C, C5′), 129.9-130.2 (m, 1C, C6′); 131.0 (C4a),132.6 (C9), 132.7-135.2 (C4′), 133.0 (C5a), 134.6 (C4), 139.4 (C9a),145.1 (C11a), 149.0 (C2), 145.3-147.9 (m, 1C, C3′), 246.8-148.3 (m, 1C,C2′), 158.1 (C7), 192.3 (C5)

EXAMPLE 1152-(2,4-Difluoro-phenylamino)-7-(R)-3,4-dihydroxy-butoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(55i)

In accordance with general method AB, 1.00 g (2.1 mmol) of2-(2,4-difluoro-phenylamino)-7-[2-(R)-2,2-dimethyl-[1,3]dioxolan-4-yl)ethoxy]-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(55h), 40 ml of MeOH, 10 ml of H2O and 0.25 g (1.3 mmol)p-toluenesulfonic acid are used.

Yield: 54%; melting point: 123° C.; C₂₅H₂₃F₂NO₄ (Mr=439.46)

IR (ATR) 3310 (N—H), 2928, 1567, 1508, 1261, 1140, 1094, 1055, 964, 845,808, 780 cm⁻¹

¹H-NMR (DMSO-d6) δ in ppm: 0.85 (s, 1H, —OH), 1.25 (s, 1H, —OH),1.52-1.98 (m, 2H, C2butanoxy-H), 2.99 (s, 4H, —CH2-CH2-), 3.55-3.63 (m,1H, C3butanoxy-H), 4.00-4.08 (m, 2 H, C4butanoxy-H), 4.53-4.60 (m, 2H,C1butanoxy-H), 6.59 (s, 1H, C1-H), 6.72 (d, 1H, J=8.6 Hz, 1H, C3-H),6.94-7.46 (m, 6H, C6-H, C8-H, C9-H, C3′-H, C5′-H, C6′-H), 7.94 (d, 1H,J=8.6 Hz, C4-H), 8.58 (s, 1H, —NH—)

¹³C-NMR (DMSO-d6) δ in ppm: 33.5 (C11), 33.5 (C2butanoxy), 36.2 (C10),65.1 (C1butanoxy), 66.3 (C4butanoxy), 68.4 (C3butanoxy), 105.3 (dd, 1C,J1=24.5 Hz, J2=27.2 Hz, C3′) 112.2 (dd, 1C, J1=3.5 Hz, J2=21.8 Hz, C5′),112.6 (C6), 113.8 (C3), 115.3 (C1), 119.1 (C8), 125.3 (dd, 1C, J1=3.1Hz, J2=11.9 Hz, C1′), 126.4 (dd 1C, J1=3.4 Hz, J2=8.6 Hz, C6′), 127.8(C4a), 130.6 (C9), 133.8 (C5a), 134.5 (C4), 139.9 (C9a), 145.7 (C11a),149.4 (C2), 156.0 (dd, 1C, J1=19.2 Hz, J2=259.8 Hz, C4′), 157.5 (C7),158.8 (dd, 1C, J1=16.1 Hz, J2=246.8 Hz, C2′), 190.8 (C5)

EXAMPLE 1167-Chloro-3-(2,4-difluorophenylamino)-6,11-dihydrodibenzo[b,e]oxepin-11-one(13)

In accordance with general method AC, 0.5 g (1.92 mmol) of3-amino-7-chloro-3,11-dihydrodibenzo[b,e]oxepin-11-one are dissolved in15 ml of toluene, and 0.08 g of2-(dicyclohexyl-phosphino)-2′,4′,6′-triisopropylbiphenyl, 0.37 g of1-bromo-2,4-difluorobenzene, 0.70 g of K-O-tert-butylate, 2 ml oftert-BuOH and finally 2 spatula tips of Pd(OAc)₂ are added. The reactionmixture is now refluxed at 100° C. under an argon atmosphere for 4 hwith TLC monitoring. The product mixture is purified by chromatographyover silica gel with hexane:EtOAc (3:1).

Yield: 52 mg (7.2%); melting point: 207.9° C.

C₂₀H₁₂ClF₂NO₂ (MR=371.8 g/mol); GC (method 1): 21.43 min

¹H-NMR (DMSO-d6): 6 (in ppm)=8.77 (s, 1H, —NH—), 7.93 (d, 1H, J=8.96 Hz,aryl H), 7.74-7.66 (m, 2H, aryl H), 7.54-7.32 (m, 3H, aryl H), 7.10 (t,1H, J=9.46 Hz, aryl H), 6.62 (d, 1 H, J=8.08 Hz, aryl H), 6.24 (s, 1H,aryl H), 5.37 (s, 2H, CH2-O—)

¹³C-NMR (DMSO-d6): δ (in ppm)=187.14 (C11), 163.05 (C4a), 160.14 (q, C2NH-Ph, J1=148.56 Hz, J2=11.80), 155.26 (q, C4 NH-Ph, J1=152.75 Hz,J2=11.80), 127, 10 (q, C6 NH-Ph, J1=9.52 Hz, J2=3.04 Hz), 124.63 (q, C1NH-Ph, J1=11.99 Hz, J2=3.23 Hz), 112.27 (q, C5 NH-Ph, J1=22.09 Hz,J2=3.81 Hz), 105.37 (q, C3 NH-Ph, J1=26.28 Hz, J2=24.00 Hz), 152.53(C3), 143.11 (C6a), 133.54 (C8), 133.11 (C1), 132.81 (C7), 131.84(C10a), 130.83 (C9), 128.12 (C10), 116.38 (C11a), 110.15 (C2), 101.75(s, C4), 68.84 (C6)

MS: m/z (%): 371(100), 336(36), 316(6), 243(7), 215(8), 203(7), 152(16),151(7), 139(8), 89(9), 63 (9)

IR (ATR): v [cm⁻¹]=3306, 1593, 1552, 1512, 1295, 1269, 1141, 1120, 841,763

1. A compound of the formula I

wherein one of the ring atoms X and Y represents CH₂ and the otherrepresents O, S, SO, SO₂ or NR5; or —X—Y— represents —CH₂—CH₂— or—CH═CH—; R1 is chosen from A) RO—, wherein R is chosen from: a)C₁-C₆-alkyl, which is substituted by 1, 2 or 3 hydroxyl or C₁-C₆-alkoxygroups; b) C₁-C₆-alkyl, which is substituted by a saturated orunsaturated, aromatic or non-aromatic heterocyclic radical having 5 or 6ring atoms, which contains 1, 2 or 3 hetero atoms which are chosenindependently of each other from O, N and S, wherein the heterocyclicradical can optionally contain 1 or 2 hydroxy, C₁-C₆-alkoxy orC₁-C₆-alkyl substituents and can be condensed with a phenyl ring or asaturated or unsaturated carbocyclic radical having 5 or 6 ring atoms;c) a non-aromatic heterocyclic radical having 5 or 6 ring atoms, whichcontains 1 or 2 hetero atoms which are chosen independently of eachother from O and N; d) C₁-C₆-alkyl; e) H; f) C₁-C₆-alkyl, which issubstituted by NR6R7; g) CF₃SO₂ ⁻; h)C₁-C₆-alkylcarbonyloxy-C₁-C₆-alkyl; and i)(C3-C7-cycloalkyl)-C₁-C₆-alkyl, which can optionally contain 1 or 2hydroxy, C₁-C₆-alkoxy or C₁-C₆-alkyl substituents on the cycloalkylradical; B) NR6R7; C) tetrazolo; and D) NR8CONR13R14; R2 represents H orC₁-C₆-alkyl; R3 is chosen from:

e) —NH—C₁-C₆-alkylene-NR6R7 f) tetrazolo; R4 represents H, halogen orC₁-C₆-alkyl; R5 represents H or C₁-C₆-alkyl, which is substituted by 1,2 or 3 hydroxyl or C₁-C₆-alkoxy groups; R6 and R7, which can beidentical or different, represent H or C₁-C₆-alkyl, which is substitutedby 1, 2 or 3 hydroxyl or C₁-C₆-alkoxy groups; R8 represents H orC₁-C₆-alkyl; R9, R10 and R11, which can be identical or different, arechosen from: a) H, b NH₂, c) mono-C₁-C₆-alkylamino, d)di-C₁-C₆-alkylamino, e) C₁-C₆-alkyl, f) C₁-C₆-alkoxy, g) hydroxyl, h)halogen, i) C₁-C₆-alkyl, which is substituted by 1, 2 or 3 halogenatoms; j) CONR6R7; and k) NO₂; R12 represents H or NH₂; R13 and R14,which can be identical or different, represent H or C₁-C₆-alkyl, ortogether with the nitrogen atom to which they are bonded form anon-aromatic heterocyclic radical having 5 or 6 ring atoms, whichcontains 1 or 2 hetero atoms which are chosen independently of eachother from O and N; and the optical isomers, physiologically acceptablesalts and solvates thereof.
 2. The compound according to claim 1 of theformula Ia

wherein Y represents O and R1, R2, R3 and R4 have the meanings given inclaim
 1. 3. The compound according to claim 1 of the formula Ib

wherein X represents O and R1, R2, R3 and R4 have the meanings given inclaim
 1. 4. The compound according to claim 1 of the formula Ic

wherein —X—Y— represents —CH₂—CH₂— or —CH═CH— and R1, R2, R3 and R4 havethe meanings given in claim
 1. 5. The compound according claim 1,wherein R1 is chosen from C₁-C₆-alkyl which is substituted by 1, 2 or 3hydroxyl groups, a saturated non-aromatic heterocyclic radical having 5or 6 ring atoms, which contains 1 or 2 hetero atoms which are chosenindependently of each other from O and N, and which can optionallycontain 1 or 2 C₁-C₆-alkyl substituents, C₁-C₆-alkoxy, hydroxyl andNR6R7.
 6. The compound according to claim 1, wherein R3 is chosen from

e) phenyl and g) tetrazolo.
 7. The compound according to claim 6,wherein R9 and R10 independently of each other are chosen from H, NH₂,mono-C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, halogen, CF₃, C₁-C₆-alkyland C₁-C₆-alkoxy and R11 represents H or halogen.
 8. The compoundaccording to claim 6, wherein R3 represents a radical of the formula


9. The compound according to claim 1, wherein R4 represents H.
 10. Thecompound according to claim 1, wherein R6 and R7 represent H.
 11. Thecompound according to claim 1 of the formula


12. The compound according to claim 2 of the formula Iaa

wherein R1, R2, R9 and R10 have the meanings given in claim
 1. 13. Thecompound according to claim 4 of the formula Ica:

wherein —X—Y— represents —CH₂—CH₂— or —CH═CH— and R1, R2, R9 and R10have the meanings given in claim
 1. 14. The compound according to claim1: (1) 2-(2-aminoanilino)-7-methoxydibenzosuberone (2)2-(2-amino-4-fluoroanilino)-7-methoxydibenzosuberone (3)2-(2,4-difluoroanilino)-7-methoxydibenzosuberone (4)2-(2-chloro-4-fluoroanilino)-7-methoxydibenzosuberone (5)2-(2,4,5-trifluoroanilino)-7-methoxydibenzosuberone (6)2-(2-trifluoromethylanilino)-7-methoxydibenzosuberone (7)2-(anilino)-7-methoxydibenzosuberone (8)2-(2-methoxyanilino)-7-methoxydibenzosuberone (9)2-(3-methyl-4-fluoroanilino)-7-methoxydibenzosuberone (10)2-(2-amino-4-trifluoromethylanilino)-7-methoxydibenzosuberone (11)2-(phenyl)-7-methoxydibenzosuberone (12)2-(2,4-difluoroanilino)-7-methoxydibenzosuberenone (13)2-(2,4-difluoroanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(14)2-(2,4-difluoroanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(15)2-(2-aminoanilino)-7-(S-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(16)2-(2-aminoanilino)-7-(R-1,2-isopropylideneglycer-3-yl)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(17)2-(2,4-difluoroanilino)-7-[2R-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(18)2-(2,4-difluoroanilino)-7-[2S-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(19)2-(2-aminoanilino-7-[2R-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(20)2-(2-aminoanilino-7-[2S-,3-dihydroxypropoxy]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(21)2-(2,4-difluoroanilino)-7-(2-hydroxy-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(22)2-(2,4-difluoroanilino)-7-(3-hydroxy-propoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(23)2-(2,4-difluoroanilino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(24)2-(2-aminoanilino)-7-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(25)2-(2,4-difluoroanilino)-7-(2-tetrahydropyran-4-yl-oxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(26)(S)-2-(2,4-difluorophenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(27)(R)-2-(2,4-difluorophenylamino)-8-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(28)(S)-2-(2-aminophenylamino)-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(29)(R)-2-(2-aminophenylamino)-8-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(30)2-(2,4-difluorophenylamino)-8-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(31)8-(2,4-difluorophenylamino)-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(32)8-(2,4-difluorophenylamino)-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(33)8-(2-aminophenylamino)-1-methoxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(34)(S)-8-(2,4-difluorophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(35)(R)-8-(2,4-difluorophenylamino)-1-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo-[a,d]cyclohepten-5-one(36)(S)-8-(2-aminophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one (37)(R)-8-(2-aminophenylamino)-1-(2,3-dihydroxypropoxy)-10,11-dihydrodibenzo-[a,d]cyclo-hepten-5-one(38)8-(2,4-difluorophenylamino)-1-(tetrahydropyran-4-yloxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one(39)8-(2,4-difluorophenylamino)-1-(2-morpholin-4-yl-ethoxy)-10,11-dihydrodibenzo-[a,d]cyclo-hepten-5-one(40) 3-(2,4-difluorophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one(41) 3-(2-aminophenylamino)-8-amino-6H-dibenzo[b,e]oxepin-11-one (42)8-amino-3-(2-methoxyphenylamino)-6H-dibenzo□b,e□oxepin-11-one (43)8-amino-3-(4-fluoro-2-methoxyphenylamino)-6H-dibenzo□b,e□-oxepin-11-one(44)8-amino-3-(2-amino-4-trifluoromethylphenylamino)-6H-dibenzo[b,e]oxepin-11-one(45) 8-amino-3-(tetrazol-1-yl)-6H-dibenzo[b,e]oxepin-11-one (46)3-(2,4-difluorophenylamino)-8-tetrazol-1-yl-6H-dibenzo[b,e]oxepin-11-one(47) 2-(2-methyl-4-Fluoroanilino)-7-methoxydibenzosuberone (48)2-(2-chloroanilino)-7-methoxydibenzosuberone (49)2-(2-amino-4-fluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(50)2-(2,4-difluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(51)2-(2-chloro-4-fluoroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(52)2-(2-chloroanilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(53) 2-(anilino)-7-hydroxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(54) 2-(2,4-difluoroanilino)-7-hydroxy-dibenzo[a,d]-cyclohepten-5-one(55)2-(2,4-difluoroanilino)-7-[3-(4-Hydroxypiperidin-4-yl-propoxy)]-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one(56)3-(2-amino-4-fluorophenylamino)-8-nitro-6H-dibenzo[b,e]oxepin-11-one(57) morpholine-4-carboxylic acid[3-(2,4-difluorophenylamino)-1-oxo-6,11-dihydrodibenzo[b,e]oxepin-8-yl]amide.15. A pharmaceutical composition containing at least one compound of theformula I according to claim 1, optionally together with physiologicallyacceptable excipients.
 16. The compound of the formula I according toclaim 1 for use in a method for immunomodulation and/or for inhibitionof the release of IL-1β and/or TNF-α.
 17. A method for immunomodulationand/or for inhibition of the release of IL-1β and/or TNF-α in a patient,wherein an active amount of a compound of the formula I according toclaim 1 is administered to the patient.